盐酸埃克替尼治疗晚期非小细胞肺癌的药理研究及Ⅰ/Ⅱa期临床研究
|
摘要
研究目的:
表皮生长因子受体(Epidermal Growth Factor Receptor,EGFR)属于Ⅰ型生长因子家族(ERRB家族),具有酪氨酸激酶活性,在非小细胞肺癌肿瘤组织上有广泛表达,从而调控肿瘤细胞的增殖、分化、凋亡和肿瘤的转移、血管增生及化疗药的耐药。其中采用EGFR酪氨酸激酶抑制剂(Epidermal Growth Factor Receptor-TyrosineKinase Inhibitor,EGFR-TKI)抑制EGFR活性是目前抗癌药研究中最受瞩目的领域。吉非替尼和厄洛替尼是目前已上市的EGFR-TKI,大型临床试验表明约9-26%的晚期非小细胞肺癌病人(Non Small Cell Lung Cancer,NSCLC)可以从中受益。盐酸埃克替尼(Icotinib Hydrochloride,BPI-2009H)是从化学库中筛选出的新的化学小分子EGFR-TKI。本研究在细胞水平,评价其对肺癌细胞毒性及作用机制,以期进一步完善其药理机制。在Ⅰ/Ⅱa期临床研究,设计晚期NSCLC,息者,分75mgTID、100mg TID、125mg TID、150mg TID四组,口服盐酸埃克替尼片,连续28天,评估其安全性和耐受性,并进一步评估稳态下盐酸埃克替尼疗效。
研究方法:
细胞水平试验观察盐酸埃克替尼对表皮生长因子(Epidermal Growth Factor,EGF)刺激引起EGFR,磷酸化EGFR(p-EGFR)表达的影响;运用xCELLigence实时监测系统检测72H内的盐酸埃克替尼对不同的肺癌细胞株的生长曲线的影响及计算IC_(50)值。本Ⅰ/Ⅱa期研究属开放、单中心、剂量递增试验(中国临床试验注册中心注册号:ChiCTR-TNRC-00000194)。病人按用药剂量75mg每8小时1次(TID)、100mg TID、125mg TID、150mg TID分4组,每个剂量组保证完成6例,由低剂量到高剂量按固定剂量口服给药方案。根据限制性毒性剂量(Dose-LimitingToxicity,DLT)的发生情况确定最大耐受剂量(Maximum Tolerated Dose,MTD)。根据临床所观察到的安全性和有效性结果资料推荐Ⅱ/Ⅲ期临床试验拟用的单药给药方案。
研究结果:
在细胞试验水平,正常HCC827细胞中有低水平的p-EGFR表达,经EGF刺激,p-EGFR表达明显升高,在埃克替尼预处理后,可以抑制EGF诱导的p-EGFR高水平表达,且随着埃克替尼的增加,p-EGFR水平明显降低,呈良好的剂量依赖效应,吉非替尼预处理产生类似作用。而两药对EGFR的表达无明显影响。在细胞毒性试验中,PC-9细胞对盐酸埃克替尼,吉非替尼两种药物敏感性高,即使在1.25mol·L~(-1)浓度,细胞也基本死亡。HCC827次之,H1650不敏感,95-D,801-D对盐酸埃克替尼,吉非替尼两种药物完全不敏感。本次临床试验从2007年12月至2009年1月共入组33例晚期非小细胞患者,按照方案,分75mg TID(225mg/天)、100mg TID(300mg/天)、125mg TID(375mg/天)、150mg TID(450mg/天)四个剂量组进行剂量递增研究。原发肿瘤TNM临床分期除3例病人未进行详细分期或Ⅲa期,其余病人均为Ⅲb期及Ⅳ期病人。33例病人既往全部至少均有一个含铂类药物治疗方案的化疗史,5例病人既往有肿瘤放疗史,3例病人有肿瘤手术史。33例受试者按方案全部纳入安全分析,以分析安全性。33例中30例完成连续28天一个周期治疗,1例病人因疾病进展提前终止试验,1例病人因家属要求提前终止试验,1例病人因违反研究方案提前终止试验。本试验对32例病人进行了初步疗效评价。在盐酸埃克替尼治疗的28天中,四个剂量组最常见的不良反应为Ⅰ或Ⅱ度的皮疹45.5%(15/33)、Ⅰ或Ⅱ度的腹泻24.2%(8/33)、Ⅰ或Ⅱ度的白细胞下降12.2%(4/33)和Ⅰ-Ⅲ度的肝转氨酶升高12.2%(4/33)。在24周时四组的按RECIST标准评价的肿瘤总体反应率ORR(CR+PR)为21.9%(7/32);疾病控制率DCR(CR+PR+SD)为43.8%(14/32)。
研究结论:
盐酸埃克替尼对EGF刺激引起的HCC827细胞中的EGFR磷酸化有抑制作用,且呈良好的剂量依赖关系;盐酸埃克替尼对不同的肺癌细胞敏感程度完全不同。在存在19外显子突变的细胞药物敏感性高,而对大细胞癌完全不敏感。在晚期非小细胞患者中,75mg TID(225mg/天)、100mg TID(300mg/天)、125mg TID(375mg/天)、150mg TID(450mg/天)四个剂量组均显示出良好的安全性和耐受性。本研究初步结果首次说明盐酸埃克替尼对于晚期非小细胞肺癌患者具有一定的疗效,但有待于Ⅱ/Ⅲ期临床试验中加以证实。125mg TID或150mg TID可以作为下阶段盐酸埃克替尼Ⅱ/Ⅲ期临床试验的治疗推荐剂量。
Background and Objective:
Targeted chemotherapies using epidermal growth factor receptor-tyrosine kinase inhibitor(EGFR-TKI) is now a well treatment for some kinds of malignancy.Gefitinib and erlotinib are approved for the treatment of patients with metastatic non-small-cell lung cancer(NSCLC).However,only 9-26%of advanced-stage NSCLC patients could benefit from treatment with these agents in clinical trials.Icotinib hydrochloride (BPI-2009H),a new selective EGFR-TKI has already demonstrated active and selective antitumor activities in both in vitro and in vivo preclinical studies.At the cellular level, the study design to assess pharmacological mechanism and cytotoxicity on several lung cancer cell lines.The phaseⅠ/Ⅱa trial design to assess the safety and tolerability of icotinib,and to explore clinical activity in patients with advanced NSCLC after failure of prior platinum-based chemotherapy.
Methods:
The evaluation of icotinib hydrochloride toxicity by a real-time cell electroni c sensing(RT-CES),the EGFR,phosphorylated EGFR(p-EGFR) expression of e pidermal growth factor(EGF)-stimulated lung cancer cell line were measured by Western -blot analysis.A phaseⅠ/Ⅱa,open-label trial(Trial registration ID:ChiC TR-TNRC-00000194 at the Chinese Clinical Trial Register).Oral icotinib(75,10 0,125,or 150 mg) was administered once 8 hours(TID) for 28-continuous day c ycle until disease progression or undue toxicity.Tumor response was assessed by RECIST.Patients continued treatment at the same dose level as long as icotinib was tolerated and there was no evidence of disease progression.
Results:
In control HCC827 cells the p-EGFR expression are low,after stimulated by EGF, EGFR expression increased markly.Icotinib hydrochloride pretreatment can inhibit EGF-induced highly p-EGFR expressed and showed a good dose-dependent effects. Gefitinib pretreatment produced a similar role.The two drugs on the expression of EGFR had no significant effect.In the cell toxicity test,PC-9 was sensitive to icotinib hydrochloride or gefitinib,even if the 1.25nM concentration,HCC827 also sensitive to both drugs.H1650 was insensitive.95-D,801-D were totally insensitive to both drugs.
From Dec 19 2007,we started the trial.The last patient finished recruitment on the Jan 2nd 2009.33 patients were enrolled.The highest treatment-related adverse events (TRAEs) were acne-like(or folliculitis) rash(15/33,45.5%),diarrhea(8/33, 24.2%),,white blood cells decreased(4/33,12.2%) and hepatic transaminases elevated(4/33,12.2%).They were mostly grade 1-2 and reversible on continuous treatment.No change in icotinib safety profile was observed with prolonged administration.None of these TRAEs were grade 4.Grade 3 TRAEs,which occurred in two patients,included hepatic transaminases elevated(one patients) at dose 100mg TID,mouth lceration(one patients) at dose 125mg TID.Maximum-tolerated dose(MTD) was not reached.32 patients were enrolled for clinical activity assess.No complete responses(CR) were observed.At the 24~(th) weeks,7 patients had PR,7 patients had SD, corresponding to a objective response rate(ORR) of 21.9%(7/32) and disease control rate(DCR) of 43.8%(14/32).
Conclusion:
Icotinib hydrochloride can inhibit EGF-induced highly p-EGFR expressed in HCC827 cell line with good dose-dependent mananer.Different lung cancer cell lines are with different sensitivity to icotinib hydrochloride.In the presence of mutations in exon 19 of cell is with the high sensitivity to icotinib hydrochloride.
Oral icotinib was generally well tolerated,with manageable and reversible AEs in patients with advanced NSCLC.Icotinib showed positive clinical anti-tumor activities in patients with advanced NSCLC.The recommended dose for phaseⅡ/Ⅲstudy with icotinib is 125mg or 150mg,TID.
表皮生长因子受体(Epidermal Growth Factor Receptor,EGFR)属于Ⅰ型生长因子家族(ERRB家族),具有酪氨酸激酶活性,在非小细胞肺癌肿瘤组织上有广泛表达,从而调控肿瘤细胞的增殖、分化、凋亡和肿瘤的转移、血管增生及化疗药的耐药。其中采用EGFR酪氨酸激酶抑制剂(Epidermal Growth Factor Receptor-TyrosineKinase Inhibitor,EGFR-TKI)抑制EGFR活性是目前抗癌药研究中最受瞩目的领域。吉非替尼和厄洛替尼是目前已上市的EGFR-TKI,大型临床试验表明约9-26%的晚期非小细胞肺癌病人(Non Small Cell Lung Cancer,NSCLC)可以从中受益。盐酸埃克替尼(Icotinib Hydrochloride,BPI-2009H)是从化学库中筛选出的新的化学小分子EGFR-TKI。本研究在细胞水平,评价其对肺癌细胞毒性及作用机制,以期进一步完善其药理机制。在Ⅰ/Ⅱa期临床研究,设计晚期NSCLC,息者,分75mgTID、100mg TID、125mg TID、150mg TID四组,口服盐酸埃克替尼片,连续28天,评估其安全性和耐受性,并进一步评估稳态下盐酸埃克替尼疗效。
研究方法:
细胞水平试验观察盐酸埃克替尼对表皮生长因子(Epidermal Growth Factor,EGF)刺激引起EGFR,磷酸化EGFR(p-EGFR)表达的影响;运用xCELLigence实时监测系统检测72H内的盐酸埃克替尼对不同的肺癌细胞株的生长曲线的影响及计算IC_(50)值。本Ⅰ/Ⅱa期研究属开放、单中心、剂量递增试验(中国临床试验注册中心注册号:ChiCTR-TNRC-00000194)。病人按用药剂量75mg每8小时1次(TID)、100mg TID、125mg TID、150mg TID分4组,每个剂量组保证完成6例,由低剂量到高剂量按固定剂量口服给药方案。根据限制性毒性剂量(Dose-LimitingToxicity,DLT)的发生情况确定最大耐受剂量(Maximum Tolerated Dose,MTD)。根据临床所观察到的安全性和有效性结果资料推荐Ⅱ/Ⅲ期临床试验拟用的单药给药方案。
研究结果:
在细胞试验水平,正常HCC827细胞中有低水平的p-EGFR表达,经EGF刺激,p-EGFR表达明显升高,在埃克替尼预处理后,可以抑制EGF诱导的p-EGFR高水平表达,且随着埃克替尼的增加,p-EGFR水平明显降低,呈良好的剂量依赖效应,吉非替尼预处理产生类似作用。而两药对EGFR的表达无明显影响。在细胞毒性试验中,PC-9细胞对盐酸埃克替尼,吉非替尼两种药物敏感性高,即使在1.25mol·L~(-1)浓度,细胞也基本死亡。HCC827次之,H1650不敏感,95-D,801-D对盐酸埃克替尼,吉非替尼两种药物完全不敏感。本次临床试验从2007年12月至2009年1月共入组33例晚期非小细胞患者,按照方案,分75mg TID(225mg/天)、100mg TID(300mg/天)、125mg TID(375mg/天)、150mg TID(450mg/天)四个剂量组进行剂量递增研究。原发肿瘤TNM临床分期除3例病人未进行详细分期或Ⅲa期,其余病人均为Ⅲb期及Ⅳ期病人。33例病人既往全部至少均有一个含铂类药物治疗方案的化疗史,5例病人既往有肿瘤放疗史,3例病人有肿瘤手术史。33例受试者按方案全部纳入安全分析,以分析安全性。33例中30例完成连续28天一个周期治疗,1例病人因疾病进展提前终止试验,1例病人因家属要求提前终止试验,1例病人因违反研究方案提前终止试验。本试验对32例病人进行了初步疗效评价。在盐酸埃克替尼治疗的28天中,四个剂量组最常见的不良反应为Ⅰ或Ⅱ度的皮疹45.5%(15/33)、Ⅰ或Ⅱ度的腹泻24.2%(8/33)、Ⅰ或Ⅱ度的白细胞下降12.2%(4/33)和Ⅰ-Ⅲ度的肝转氨酶升高12.2%(4/33)。在24周时四组的按RECIST标准评价的肿瘤总体反应率ORR(CR+PR)为21.9%(7/32);疾病控制率DCR(CR+PR+SD)为43.8%(14/32)。
研究结论:
盐酸埃克替尼对EGF刺激引起的HCC827细胞中的EGFR磷酸化有抑制作用,且呈良好的剂量依赖关系;盐酸埃克替尼对不同的肺癌细胞敏感程度完全不同。在存在19外显子突变的细胞药物敏感性高,而对大细胞癌完全不敏感。在晚期非小细胞患者中,75mg TID(225mg/天)、100mg TID(300mg/天)、125mg TID(375mg/天)、150mg TID(450mg/天)四个剂量组均显示出良好的安全性和耐受性。本研究初步结果首次说明盐酸埃克替尼对于晚期非小细胞肺癌患者具有一定的疗效,但有待于Ⅱ/Ⅲ期临床试验中加以证实。125mg TID或150mg TID可以作为下阶段盐酸埃克替尼Ⅱ/Ⅲ期临床试验的治疗推荐剂量。
Background and Objective:
Targeted chemotherapies using epidermal growth factor receptor-tyrosine kinase inhibitor(EGFR-TKI) is now a well treatment for some kinds of malignancy.Gefitinib and erlotinib are approved for the treatment of patients with metastatic non-small-cell lung cancer(NSCLC).However,only 9-26%of advanced-stage NSCLC patients could benefit from treatment with these agents in clinical trials.Icotinib hydrochloride (BPI-2009H),a new selective EGFR-TKI has already demonstrated active and selective antitumor activities in both in vitro and in vivo preclinical studies.At the cellular level, the study design to assess pharmacological mechanism and cytotoxicity on several lung cancer cell lines.The phaseⅠ/Ⅱa trial design to assess the safety and tolerability of icotinib,and to explore clinical activity in patients with advanced NSCLC after failure of prior platinum-based chemotherapy.
Methods:
The evaluation of icotinib hydrochloride toxicity by a real-time cell electroni c sensing(RT-CES),the EGFR,phosphorylated EGFR(p-EGFR) expression of e pidermal growth factor(EGF)-stimulated lung cancer cell line were measured by Western -blot analysis.A phaseⅠ/Ⅱa,open-label trial(Trial registration ID:ChiC TR-TNRC-00000194 at the Chinese Clinical Trial Register).Oral icotinib(75,10 0,125,or 150 mg) was administered once 8 hours(TID) for 28-continuous day c ycle until disease progression or undue toxicity.Tumor response was assessed by RECIST.Patients continued treatment at the same dose level as long as icotinib was tolerated and there was no evidence of disease progression.
Results:
In control HCC827 cells the p-EGFR expression are low,after stimulated by EGF, EGFR expression increased markly.Icotinib hydrochloride pretreatment can inhibit EGF-induced highly p-EGFR expressed and showed a good dose-dependent effects. Gefitinib pretreatment produced a similar role.The two drugs on the expression of EGFR had no significant effect.In the cell toxicity test,PC-9 was sensitive to icotinib hydrochloride or gefitinib,even if the 1.25nM concentration,HCC827 also sensitive to both drugs.H1650 was insensitive.95-D,801-D were totally insensitive to both drugs.
From Dec 19 2007,we started the trial.The last patient finished recruitment on the Jan 2nd 2009.33 patients were enrolled.The highest treatment-related adverse events (TRAEs) were acne-like(or folliculitis) rash(15/33,45.5%),diarrhea(8/33, 24.2%),,white blood cells decreased(4/33,12.2%) and hepatic transaminases elevated(4/33,12.2%).They were mostly grade 1-2 and reversible on continuous treatment.No change in icotinib safety profile was observed with prolonged administration.None of these TRAEs were grade 4.Grade 3 TRAEs,which occurred in two patients,included hepatic transaminases elevated(one patients) at dose 100mg TID,mouth lceration(one patients) at dose 125mg TID.Maximum-tolerated dose(MTD) was not reached.32 patients were enrolled for clinical activity assess.No complete responses(CR) were observed.At the 24~(th) weeks,7 patients had PR,7 patients had SD, corresponding to a objective response rate(ORR) of 21.9%(7/32) and disease control rate(DCR) of 43.8%(14/32).
Conclusion:
Icotinib hydrochloride can inhibit EGF-induced highly p-EGFR expressed in HCC827 cell line with good dose-dependent mananer.Different lung cancer cell lines are with different sensitivity to icotinib hydrochloride.In the presence of mutations in exon 19 of cell is with the high sensitivity to icotinib hydrochloride.
Oral icotinib was generally well tolerated,with manageable and reversible AEs in patients with advanced NSCLC.Icotinib showed positive clinical anti-tumor activities in patients with advanced NSCLC.The recommended dose for phaseⅡ/Ⅲstudy with icotinib is 125mg or 150mg,TID.
引文
[1] Kumar A, Petri ET, Halmos B, et al. Structure and clinical relevance of the epidermal growth factor receptor in human cancer. J Clin Oncol. 2008;26(10):1742-1751.
[2] Karamouzis MV, Grandis JR, Argiris A. Therapies Directed Against Epidermal Growth Factor Receptor in Aerodigestive Carcinomas. JAMA. 2007;298(1):70-82.
[3] Ciardiello F, Tortora G.. A novel approach in the treatment of cancer: targeting the epidermal growth factor receptor. Clin Cancer Res. 2001;7(10):2958-70.
[4] Xiong X, Liu H, Fu L, et al. Antitumor activity of a new N-substituted thiourea derivative, an EGFR signaling-targeted inhibitor against a panel of human lung cancer cell lines. Chemotherapy. 2008;54(6):463-474.
[5] Abassi YA, Xi B, Zhang W, et al. Kinetic cell-based morphological screening:prediction of mechanism of compound action and off-target effects. Chem Biol.2009;16(7):712-23.
[6] Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005;352(8):786-92.
[7] Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2(3):e73.
[8] Yoshida T, Okamoto I, Okamoto W, et al. Effects of Src inhibitors on cell growth and epidermal growth factor receptor and MET signaling in gefitinib-resistant non-small cell lung cancer cells with acquired MET amplification. Cancer Sci.2009 Sep 14.(Epub ahead of print)
[9] Lynch, TJ, Bell, DW, Sordella, R, et al.Activating mutations in the epidermal growth factor receptor underlyingresponsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350, 2129-2139.
[10] aez J G,Janne P A,Lee J C,et al.EGFR mutation in lung cancer:correlation with clicical response to gefitinib therapy.Science.2004;304:1497.
[11] Helfrich BA, Raben D, Varella-Garcia M, et al. AntitumorActivity of the Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor Gefitinib (ZD1839, Iressa) in Non-Small Cell Lung Cancer Cell Lines Correlates with Gene Copy Number and EGFR Mutations but not EGFR Protein Levels.Clin Cancer Res. 2006;12(23):7117-7125.
[12] Gandhi J, Zhang J, Xie Y, et al. Alterations in genes of the EGFR signaling pathway and their relationship to EGFR tyrosine kinase inhibitor sensitivity in lung cancer cell lines. PLoS One. 2009;4(2):e4576.
[13] Nahta R, Yu D, Hung MC, et al. Mechanisms of disease: understanding resistance to HER2 targeted therapy in human breast cancer. Nat Clin Pract Oncol.2006;3(5):269-280.
[14] Smith I, Procter M, Gelber RD, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet. 2007;369(9555):29-36.
[15] Cully M, You H, Levine AJ, et al. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer. 2006;6(3):184-192.
[16] Bianco R, Shin I, Ritter CA, et al. Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene. 2003;22(18):2812-2822.
[17] Nagata Y, Lan KH, Zhou X, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients.Cancer Cell. 2004;6(2):117-127.
[18] She QB, Solit D, Basso A, et al. Resistance to gefitinib in PTEN-null HER-overexpressing tumor cells can be overcome through restoration of PTEN function or pharmacologic modulation of constitutive phosphatidylinositol 3'-kinase/Akt pathway signaling. Clin Cancer Res. 2003;9(12):4340-4346.
[19] Sos ML, Koker M, Weir BA, et al. PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res. 2009;69(8):3256-3261.
[1]全国肿瘤防治研究办公室,全国肿瘤登记中心,卫生部疾病预防控制局主编.中国部分市县1998-2002年恶性肿瘤发病与死亡(第三卷).北京:人民卫生出版社,2007:290-295.
[2]Dempke WC,Suto T,Reck M.Targeted therapies for non-small cell lung cancer.Lung Cancer.2010;67(3):257-274.
[3]Karamouzis MV,Grandis JR,Argiris A.Therapies directed against epidermal growth factor receptor in aerodigestive carcinomas.JAMA.2007;298(1):70-82.
[4]Ciardiello F,Tortora G.A novel approach in the treatment of cancer:targeting the epidermal growth factor receptor.Clin Cancer Res.2001;7(10):2958-2970.
[5]Unscramble Statistical Analysis on Large Clinical Trials- IRESSA Survival Evaluation in Lung Cancer(ISEL) / AstraZeneca Pharmaceutical Co.Ltd.
[6]Shepherd FA,Rodrigues Pereira J,Ciuleanu T,et al.Erlotinib in previously treated non-small-cell lung cancer.N Engl J Med.2005;353(2):123-132.
[7]Fukuoka M,Yano S,Giaccone G,et al.Multi-institutional randomized phase Ⅱtrial of gefitinib for previously treated patients with advanced non-small-cell lung cancer(The IDEAL 1 Trial)[corrected].J Clin Oncol.2003;21:2237-2246.
[8]Perez-Soler R,Chachoua A,Hammond LA,et al.Determinants of tumor response and survival with erlotinib in patients with non-smallcell lung cancer.J Clin Oncol.2004;22:3238 - 3247.
[9]Lynch TJ,Bell DW,Sordella R,et al.Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.N Engl J Med.2004;350:2129-2139.
[10]Cho BC,Im CK,Park MS,et al.Phase Ⅱ study of erlotinib in advanced non-small-cell lung cancer after failure of gefitinib. J Clin Oncol. 2007;25:2528-2533.
[11] Gridelli C, Maione P, Galetta D, et al. Three cases of long-lasting tumor control with erlotinib after progression with gefitinib in advanced non-small cell lung cancer. J Thorac Oncol .2007;2: 758-761.
[12] Choong NW, Dietrich S, Seiwert TY, et al. Gefitinib response of erlotinib-refractory lung cancer involving meninges - role of EGFR mutation. Nat Clin Pract Oncol. 2006; 3:50-57.
[13] Garfield DH, Modern treatment of lung cancer: case 2. Response to erlotinib after failure of gefitinib in a patient with advanced nonsmall-cell lung carcinoma. J Clin Oncol. 2005; 23: 7738-7740.
[14] Sweeney CJ, Zhu J, Sandier AB, et al.Outcome of patients with a performance status of 2 in Eastern Cooperative Oncology Group Study E1594: a Phase II trial in patients with metastatic nonsmall cell lung carcinoma.Cancer.2001;92:2639-2647.
[15] Cohen MH, Johnson JR, et al. FDA Drug Approval Summary: Erlotinib (Tarceva) Tablets. The Oncologist. 2005; 10:461-466.
[16] Cohen MH,Williams GA,Sridhara R,et.al.United States Food and Drug Administration Drug Approval Summary: Gefitinib (ZD1839; Iressa) Tablets.Clinical Cancer Research. 2004;10:1212-1218.
[17] Nakagawal K, Tamura T, Negoro S, et al. Phase I pharmacokinetic trial of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) in Japanese patients with solid malignant tumors. Annals of Oncology. 2003; 14: 922-930,.
[18] Hidalgo M, Siu LL, Nemunaitis J, et. al. Phase I and Pharmacologic Study of OSI-774, an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients with Advanced Solid Malignancies.J Clin Oncol. 2001;19(13):3267-3279.
[19] Ranson M, Hammond LA, Ferry D,et al. ZD1839, a Selective Oral Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor, is Well Tolerated and Active in Patients with Solid, Malignant Tumors: Results of a Phase I Trial. J Clin Oncol.2002;20(9):2240-2250.
[1] Ramalingam S, Belani C. Systemic chemotherapy for advanced non-small cell lung cancer: recent advances and future directions. Oncologist. 2008;15:5—13.
[2] Rudd RM, Gower NH, Spiro SG, et al. Gemcitabineplus carboplatin versus mitomycin, ifosfamide, and cisplatin in patients with stage IIIB or IV non small cell lung cancer.Aphase III randomized study of the London Cancer Group. J Clin Oncol. 2005;23:142-153.
[3] Martoni A, Marino A, Sperandi F, et al. Multicentre randomized phase III study comparing the same dose and schedule of cisplatin plus the same schedule of vinorelbine or gemcitabine in advanced non-small cell lung cancer. Eur J Cancer 2005:41:81-92.
[4] Marmor MD, Skaria KB, Yarden Y. Signal transduction and oncogenesis by ErbB/HER receptors Int J Radiat Oncol Biol Phys.2004;58:903-913.
[5] Kris MG Natale RB, Herbst RS, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA. 2003;290(16):2149 -2158.
[6] Grunwald V, Hidalgo M. Development of the epidermal growth factor receptor inhibitor Tarceva (OSI-774). Adv Exp Med Biol. 2003;532:235-246.
[7] Lynch, TJ, Bell, DW, Sordella, R , et al..Activating mutations in the epidermal growth factor receptor underlyingresponsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350, 2129-2139.
[8] Paez J G,Janne P A,Lee J C.et al.EGFR mutation in lung cancer:correlation with clicical response to gefitinib therapy.Science.2004;304:1497.
[9] Tracy S,Mukohara T,Hansen M,et al.Gefitinib induces apoptosis in EGFRL858R non-small cell lung cancer line H3255.Cancer Rec.2004;64:7241.
[10] Pao,W., Miller, V., Zakowski, et al.. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc. Natl. Acad. Sci. 2004;101,13306-13311.
[11] Han S W,Kin T Y.Hwang P Get al.Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small cell cancer patients treated with gefitinib. J Clin Oncol.2005;23:l.
[12] Bianco R, Troiani T, Tortora G, et al. Intrinsic and acquired resistance to EGFR inhibitors in human cancer therapy. Endocr Relat Cancer.2005;12:S159- S171.Engelman JA, Mukohara T, Zejnullahu K, et al. A llelic dilution obscures detection of a b iologically significant resistance mutation in EGFR- amplified lung cancer.Journal of Clinical Investigation.2006;116: 2695-2706.
[13] Riely GJ, Marks J, Pao W. KRAS mutations in non-small cell lung cancer. Proc Am Thorac Soc. 2009;6:201-205.
[14] Pao, W, Wang, TY, Riely, GJ, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med. 2005;2:el7.
[15] Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to Gefitinib. N EngJ J Med. 2005;352:786-792.
[16] Inukai M, Toyooka S, Ito S,et al. Presence of epidermal growth factor receptor gene T790M nmtation as a nlinor clone in non-small cell lung cancer, Cancer Res.2006; 66:7854-7858.
[17] Wu SG Chang YL, Hsu YC, et al. Good response to gefitinib in lung adenocarcinoma of complex epidermal growth factor receptor (EGFR) mutations with the classical mutation pattern. Oncologist.2008;13:1276-1284.
[18] Birchmeier C, Birchmeier W, Gherardi E, et al. Met, metastasis, motility and more. Nat Rev Mol Cell Biol. 2003; 4:915-925.
[19] Ido, A. and Tsubouchi, H. Translational research to identify clinical applications of hepatocyte growth factor. Hepatol Res. 2009; 39;739-747.
[20] Giebeler, A. et al. c-Met confers protection against chronic liver tissue damage and fibrosis progression after bile duct ligation in mice.Gastroenterology.2009;137:297-308.
[21] Christensen, J. et al. c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett. 2005; 8:1-26.
[22] Liu, X. et al. Targeting the c-MET signaling pathway for cancer therapy. Expert Opin Investig Drugs. 2008; 17:997-1011.
[23] Zeng, Z.S. et al. c-Met gene amplification is associated with advanced stage colorectal cancer and liver metastases. Cancer Lett. 2008; 265:258-269.
[24] Seiwert, T.Y. et al.The MET receptor tyrosine kinase is a potential novel therapeutic target for head and neck squamous cell carcinoma. Cancer Res. 2009;69:3021-3031.
[25] Knowles, L.M. et al. HGF and c-Met participate in paracrine tumorigenic pathways in head and neck squamous cell cancer. Clin Cancer Res. 2009; 15:3740-3750.
[26] Okuda, K. et al. Met gene copy number predicts the prognosis for completely resected non-small cell lung cancer. Cancer Sci. 2008;99;2280-2285.
[27] Toiyama, Y. et al. Serum hepatocyte growth factor as a prognostic marker for stage II or III colorectal cancer patients. Int J Cancer. 2009; 125:1657-1662.
[28] Gupta, A. et al. Predictive value of plasma hepatocyte growth factor/scatter factor levels in patients with clinically localized prostate cancer. Clin Cancer Res.2008; 14:7385-7390.
[29] Cappuzzo, F. et al. Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients. J Clin Oncol. 2009;27:1667-1674.
[30] Kammula, U.S. et al. Molecular co-expression of the c-Met oncogene and hepatocyte growth factor in primary colon cancer predicts tumor stage and clinical outcome. Cancer Lett. 2007;248: 219-228.
[31] Miyata, Y. et al. Phosphorylated hepatocyte growth factor receptor/c-Met is associated with tumor growth and prognosis in patients with bladder cancer:correlation with matrix metalloproteinase-2 and -7 and E-cadherin. Hum Pathol.2009;40:496-504.
[32] Engehnan JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to Gefitinib resistance in lung cancer by activating ERBB3 signaling. Science.2007;316:1039-1043.
[33] Engehnan JA, Mukohara T, Zejnullahu K, et al. Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. J Clin Invest. 2006;116:2695-2706.
[34] Bean J, Brennan C, Shih JY, et al. MET amplification occurs with or without T790M nlutations in EGFR mutant lung tumors with acquired resistance to Gefitinib or Erlotinib. Proc Natl Acad Sci USA. 2007;104(52):20932-20937.
[35] Engehnan JA, Janne PA, Mermel C, et al. ErbB-3 mediates phO phOinOsitide 3-kinase activity in Gefitinib. sensitive non. small cell lung cancer cell lines[J].Proc Natl Acad Sci USA. 2005; 102:3788-3793.
[36] Janmaat, ML, Kruyt, FA, Rodriguez, JA, et al. Response to epidermal growth factor receptor inhibitors in non-small cell lung cancer cells: limited antiproliferative effects and absence of apoptosis associated with persistent activity of extracellular signal-regulated kinase or Akt kinase pathways. Clin.Cancer Res. 2003; 9, 2316-2326.
[37] Vivanco, I, Sawyers, C.L. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat. Rev. Cancer. 2002;2: 489-501.
[38] Cully,M,You, H, Levine, AJ, et al. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis.Nat Rev Cancer.2006;6:184-192.
[39] Bianco, R, Shin, I, Ritter, CA, et al.Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene. 2003; 22:2812-2822.
[40] Nagata Y, Lan KH , Zhou X , et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004; 6:117-127.
[41] She QB, Solit D, Basso A, et al. Resistance to gefitinib in PTEN-null HER-overexpressing tumor cells can be overcome through restoration of PrEN function or pharmaeologie modulation of constitutive phosphatidylinositol 3 —kinase / Akt pathway signaling. Clin Cancer Res.2003; 9:4340-4346.
[42] Sos ML, Koker M, Weir BA, et al. PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR.Cancer Res. 2009 Apr 15;69:3256-3261.
[43] Samani, AA, Yakar, S, Leroith, D, et al.The Role of the IGF System in Cancer Growth and Metastasis: Overviewand Recent Insights. Endocr. Rev. 2007; 28,20-47.
[44] Takahashi, Y, Bucana, CD, Liu, W, et al.Platelet-derived endothelial cell growth factor in human colon cancer angiogenesis: role of infiltrating cells. J Natl Cancer Inst. 1996; 88: 1146-1151.
[45] Morgillo, F, Lee, HY, Resistance to epidermal growth factor receptor-targeted therapy. Drug Resist Updat. 2005; 8:298-310.
[46] Sandier AB, Johnson DH, Herbst RS. Anti-vascular endothelial growth factor monoclonals in non-small cell lung cancer. Clin Cancer Res. 2004; 10:s4258-4262.
[47] Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003;3:401-410.
[48] Viloria-Petit A, Crombet T, Jothy S, et al.Acquired resistance to the antitumor effect of epidermal growth factor receptorblocking antibodies in vivo: A role for altered tumor angiogenesis. Cancer Res. 2001;61:5090-5101.
[49] Bianco R, Rosa R, Damiano V, et al. Vascular endothelial growth factor receptor-1 contributes to resistance to anti-epidermal growth factor receptor drugs in human cancer cells. Clin Cancer Res. 2008; 14:5069-5080.
[50] Roy M. Bremnes, Carlos Camps, Rafael Sirera .Angiogenesis in non-small cell lung cancer: The prognostic impact of neoangiogenesis and the cytokines VEGF and bFGF in tumours and blood. Lung Cancer. 2006;51:143-158.
[51] Dempke WCM, Heinemann V. Resistance to EGF-R (erbB-1) and VEGF-R modulating agents. Eur J Cancer 2009;45:1117-1128.
[52] Guix M, Faber RC, Wang SE, et al. Acquired resistance to EGFR-tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J Clin Invest.2008;118:2609-2619.
[53] Shi Z, Parmar S, Peng XX, et al. The epidermal growth factor tyrosine kinase inhibitor AG1478 and erlotinib reverse ABCG2-mediated drug resistance. Oncol Rep.2009;21:483-489.
[54] Dai CL, Tiwari AK, Wu CP, et al. Lapatinib (Tykerb,GW572016) reverses multidrug resistance in cancer cells by inhibiting the activity of ATP-binding cassette subfamily B member 1 and G member 2. Cancer Res. 2008;68:7905-7914.
[55] Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004;22:2184-2191.
[56] Sandier A, Gray R, Perry MC, et al. Paclitaxelcarboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542-2550.
[57] Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAiL. J Clin Oncol. 2009;27:1227-1234.
[58] Hainsworth J, Herbst R. A phase III multicenter, placebo-controlled, doubleblind,randomized clinical trial to evaluate the efficacy of bevacizumab (Avastin`) in combination with erlotinib (Tarceva`) compared with erlotinib alone for treatment of advanced non-small cell lung cancer after failure of standard first-line chemotherapy (BETA). J Thorac Oncol. 2008;3(Suppl. 4):S302.
[59] Laurie SA, Gauthier I, Arnold A, et al. Phase I and pharmacokinetic study of daily oral AZD2171, an inhibitor of vascular endothelial growth factor tyrosine kinases,in combination with carboplatin and paclitaxel in patients with advanced non-small-cell lung cancer: The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2008;26:1871-1878.
[60] Laurie SA, Arnold A, Shepherd FA, et al. Randomizes,double-blind phase II trial of carboplatin + paclitaxel (C + P) with either daily oral cediranib, an inhibitor of vascular endothelial growth factor receptor [VEGFR] tyrosine kinases. Ann Oncol. 2009;19(Suppl. 8):90-91.
[61] Freiwald M, Liesenfeld K, Bruno R C, et al. Population pharmacokinetic analysis for BIBF 1120, an angiokinase inhibitor,in patients with advanced non-small-cell lung cancer (NSCLC). J Clin Oncol. 2008;26(Suppl.): 14528.
[62] Bahleda R, Soria J, Harbison C, et al. Tumor regression and pharmacodynamic (PD) biomarker validation in non-small cell lung cancer (NSCLC) patients treated with the ErbB/VEGFR inhibitor BMS-690514. J Clin Oncol.2009;27(Suppl.):431s.
[63] Carter, CA, Chen, C, Brink, C, et al.Sorafenib is efficacious and tolerated in combination with cytotoxic or cytostatic agents in preclinical models of human non-small cell lung carcinoma. Cancer Chemother. Pharmacol. 2007;59:183-195.
[64] Adjei, AA, Mandrekar, S, Marks, RS, et al.A Phase I study of BAY 43-9006 and gefitinib in patients with refractory or recurrent non-small-cell lung cancer (NSCLC). J. Clin. Oncol. 2005;23:3067 (abstract).
[65] Li D, Shimamura T, Ji H, et al. Bronchial and peripheral murine lung carcinomas induced by T790M-L858R mutant EGFR respond to HKI—272 and Rapamycin combination therapy. Cancer Cell. 2007; 12:81—93.
[66] Heymach JV, Johnson DH, Khuri FR, et al. Phase II study of the farnesyl transferase inhibitor R115777 in patients with sensitive relapse small cell lung cancer.Ann Oncol 2004; 15:1187-1193.
[67] Hewish M, Chau I, Cunningham D. Insulin-like growth factor 1 receptor targeted therapeutics: novel compounds and novel treatment strategies for cancer medicine.Recent Pat Anticancer Drug Discov 2009;4:54-72.
[68] Haluska P, Shaw HM, Batzel GN,et al. Phase I dose escalation trial of the anti insulin-like growth factor-I receptor monoclonal antibody CP-751,871 in patients with refractory solid tumors. Clin Cancer Res. 2007; 13:5834-5840.
[69] Lacy MQ, Alsina M, Fonseca R, et al. Phase I,pharmacokinetic and pharmacodynamic study of the anti-insulin like growth factor type 1 receptor monoclonal antibody CP-751,871 in patients with multiple myeloma. J Clin Oncol.2008;26:3196-3202.
[70] Karp DD, Paz-Ares LG, Novello S, et al. Phase II study of the anti-insulin-likegrowth factor type 1 receptor antibody CP-751,871 in combination with paclitaxel and carboplatin in previously untreated, locally advanced, or metastatic non-small-cell lung cancer. J Clin Oncol. 2009;27: 2515-2522.
[71] Han JY, Choi BG, Choi JY, et al. The prognostic significance of pretreatment plasma levels of insulin-like growth factor (IGF)-1, IGF-2, and IGF binding protein-3 in patients with advanced non-small cell lung cancer. Lung Cancer.2006;54:227-234.
[72] Kwak EL, Sordella R, Bell DW, et al. Irreversible inhibitors of the EGF receptor may cireunlvent acquired resistance to Gefitinib. Proc Natl Acad Sci USA.2005;102(21 ):7665—7670.
[73] Yang C, Hirsh V, Cadranel J, et al. Phase IIb/III doubleblind randomized trial of BIBW 2992, an irreversible, dual inhibitor of EGFR and HER2 plus best supportive care (BSC) versus placebo plus BSC in patients with NSCLC failing 1-2 lines of chemotherapy (CT) and erlotinib or gefitinib (LUX-Lung 1): a preliminary report. J Clin Oncol 2009;27(Suppl.):422s.
[74] Janne, PA. et al. Targeting MET with XL184 to reverse EGFR tyrosine kinase inhibitor (TKI) resistance in NSCLC: impact of preclinical studies on clinical trial design. European J of Cancer. 2008,Abstract 552
[75] Reardon, D.A. et al. Phase II study of AMG102, a fully human neutralizing antibody against hepatocyte growth factor/scatter factor, in patients with recurrent glioblastoma multiforme, In The ASCO Annual Meeting, 2008,Abstract 2051
[76] Ritossa, F. Discovery of the heat shock response. Cell Stress Chaperon. 1996;1:97-98.
[77] Westerheide, SD, Morimoto, RI,. Heat shock response modulators as therapeutic tools for diseases of protein conformation. J Biol Chem. 2005;280:33097- 33100.
[78] Pearl, LH, Prodromou, C, Workman, P. The Hsp90 molecular chaperone: an open and shut case for treatment. Biochem J. 2008;410:439-453.
[79] Didelot, C, Lanneau, D, Brunet, M, et al.. Anti-cancer therapeutic approaches based on intracellular and extracellular heat shock proteins. Curr Med Chem.2007; 14:2839-2847.
[80] Supko, JG, Hickman, RL, Grever, M. , et al. Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent. Cancer Chemother. Pharmacol.1995;36:305-315.
[81] Bao R, Lai CJ, Wang DG, et al.Targeting heat shock protein 90 with CUDC-305 overcomes erlotinib resistance in non-small cell lung cancer Mol. Cancer Ther.,December 1, 2009; 8: 3296 - 3306.
[2] Karamouzis MV, Grandis JR, Argiris A. Therapies Directed Against Epidermal Growth Factor Receptor in Aerodigestive Carcinomas. JAMA. 2007;298(1):70-82.
[3] Ciardiello F, Tortora G.. A novel approach in the treatment of cancer: targeting the epidermal growth factor receptor. Clin Cancer Res. 2001;7(10):2958-70.
[4] Xiong X, Liu H, Fu L, et al. Antitumor activity of a new N-substituted thiourea derivative, an EGFR signaling-targeted inhibitor against a panel of human lung cancer cell lines. Chemotherapy. 2008;54(6):463-474.
[5] Abassi YA, Xi B, Zhang W, et al. Kinetic cell-based morphological screening:prediction of mechanism of compound action and off-target effects. Chem Biol.2009;16(7):712-23.
[6] Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. N Engl J Med. 2005;352(8):786-92.
[7] Pao W, Miller VA, Politi KA, et al. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med. 2005;2(3):e73.
[8] Yoshida T, Okamoto I, Okamoto W, et al. Effects of Src inhibitors on cell growth and epidermal growth factor receptor and MET signaling in gefitinib-resistant non-small cell lung cancer cells with acquired MET amplification. Cancer Sci.2009 Sep 14.(Epub ahead of print)
[9] Lynch, TJ, Bell, DW, Sordella, R, et al.Activating mutations in the epidermal growth factor receptor underlyingresponsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350, 2129-2139.
[10] aez J G,Janne P A,Lee J C,et al.EGFR mutation in lung cancer:correlation with clicical response to gefitinib therapy.Science.2004;304:1497.
[11] Helfrich BA, Raben D, Varella-Garcia M, et al. AntitumorActivity of the Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor Gefitinib (ZD1839, Iressa) in Non-Small Cell Lung Cancer Cell Lines Correlates with Gene Copy Number and EGFR Mutations but not EGFR Protein Levels.Clin Cancer Res. 2006;12(23):7117-7125.
[12] Gandhi J, Zhang J, Xie Y, et al. Alterations in genes of the EGFR signaling pathway and their relationship to EGFR tyrosine kinase inhibitor sensitivity in lung cancer cell lines. PLoS One. 2009;4(2):e4576.
[13] Nahta R, Yu D, Hung MC, et al. Mechanisms of disease: understanding resistance to HER2 targeted therapy in human breast cancer. Nat Clin Pract Oncol.2006;3(5):269-280.
[14] Smith I, Procter M, Gelber RD, et al. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet. 2007;369(9555):29-36.
[15] Cully M, You H, Levine AJ, et al. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis. Nat Rev Cancer. 2006;6(3):184-192.
[16] Bianco R, Shin I, Ritter CA, et al. Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene. 2003;22(18):2812-2822.
[17] Nagata Y, Lan KH, Zhou X, et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients.Cancer Cell. 2004;6(2):117-127.
[18] She QB, Solit D, Basso A, et al. Resistance to gefitinib in PTEN-null HER-overexpressing tumor cells can be overcome through restoration of PTEN function or pharmacologic modulation of constitutive phosphatidylinositol 3'-kinase/Akt pathway signaling. Clin Cancer Res. 2003;9(12):4340-4346.
[19] Sos ML, Koker M, Weir BA, et al. PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res. 2009;69(8):3256-3261.
[1]全国肿瘤防治研究办公室,全国肿瘤登记中心,卫生部疾病预防控制局主编.中国部分市县1998-2002年恶性肿瘤发病与死亡(第三卷).北京:人民卫生出版社,2007:290-295.
[2]Dempke WC,Suto T,Reck M.Targeted therapies for non-small cell lung cancer.Lung Cancer.2010;67(3):257-274.
[3]Karamouzis MV,Grandis JR,Argiris A.Therapies directed against epidermal growth factor receptor in aerodigestive carcinomas.JAMA.2007;298(1):70-82.
[4]Ciardiello F,Tortora G.A novel approach in the treatment of cancer:targeting the epidermal growth factor receptor.Clin Cancer Res.2001;7(10):2958-2970.
[5]Unscramble Statistical Analysis on Large Clinical Trials- IRESSA Survival Evaluation in Lung Cancer(ISEL) / AstraZeneca Pharmaceutical Co.Ltd.
[6]Shepherd FA,Rodrigues Pereira J,Ciuleanu T,et al.Erlotinib in previously treated non-small-cell lung cancer.N Engl J Med.2005;353(2):123-132.
[7]Fukuoka M,Yano S,Giaccone G,et al.Multi-institutional randomized phase Ⅱtrial of gefitinib for previously treated patients with advanced non-small-cell lung cancer(The IDEAL 1 Trial)[corrected].J Clin Oncol.2003;21:2237-2246.
[8]Perez-Soler R,Chachoua A,Hammond LA,et al.Determinants of tumor response and survival with erlotinib in patients with non-smallcell lung cancer.J Clin Oncol.2004;22:3238 - 3247.
[9]Lynch TJ,Bell DW,Sordella R,et al.Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib.N Engl J Med.2004;350:2129-2139.
[10]Cho BC,Im CK,Park MS,et al.Phase Ⅱ study of erlotinib in advanced non-small-cell lung cancer after failure of gefitinib. J Clin Oncol. 2007;25:2528-2533.
[11] Gridelli C, Maione P, Galetta D, et al. Three cases of long-lasting tumor control with erlotinib after progression with gefitinib in advanced non-small cell lung cancer. J Thorac Oncol .2007;2: 758-761.
[12] Choong NW, Dietrich S, Seiwert TY, et al. Gefitinib response of erlotinib-refractory lung cancer involving meninges - role of EGFR mutation. Nat Clin Pract Oncol. 2006; 3:50-57.
[13] Garfield DH, Modern treatment of lung cancer: case 2. Response to erlotinib after failure of gefitinib in a patient with advanced nonsmall-cell lung carcinoma. J Clin Oncol. 2005; 23: 7738-7740.
[14] Sweeney CJ, Zhu J, Sandier AB, et al.Outcome of patients with a performance status of 2 in Eastern Cooperative Oncology Group Study E1594: a Phase II trial in patients with metastatic nonsmall cell lung carcinoma.Cancer.2001;92:2639-2647.
[15] Cohen MH, Johnson JR, et al. FDA Drug Approval Summary: Erlotinib (Tarceva) Tablets. The Oncologist. 2005; 10:461-466.
[16] Cohen MH,Williams GA,Sridhara R,et.al.United States Food and Drug Administration Drug Approval Summary: Gefitinib (ZD1839; Iressa) Tablets.Clinical Cancer Research. 2004;10:1212-1218.
[17] Nakagawal K, Tamura T, Negoro S, et al. Phase I pharmacokinetic trial of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor gefitinib ('Iressa', ZD1839) in Japanese patients with solid malignant tumors. Annals of Oncology. 2003; 14: 922-930,.
[18] Hidalgo M, Siu LL, Nemunaitis J, et. al. Phase I and Pharmacologic Study of OSI-774, an Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients with Advanced Solid Malignancies.J Clin Oncol. 2001;19(13):3267-3279.
[19] Ranson M, Hammond LA, Ferry D,et al. ZD1839, a Selective Oral Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor, is Well Tolerated and Active in Patients with Solid, Malignant Tumors: Results of a Phase I Trial. J Clin Oncol.2002;20(9):2240-2250.
[1] Ramalingam S, Belani C. Systemic chemotherapy for advanced non-small cell lung cancer: recent advances and future directions. Oncologist. 2008;15:5—13.
[2] Rudd RM, Gower NH, Spiro SG, et al. Gemcitabineplus carboplatin versus mitomycin, ifosfamide, and cisplatin in patients with stage IIIB or IV non small cell lung cancer.Aphase III randomized study of the London Cancer Group. J Clin Oncol. 2005;23:142-153.
[3] Martoni A, Marino A, Sperandi F, et al. Multicentre randomized phase III study comparing the same dose and schedule of cisplatin plus the same schedule of vinorelbine or gemcitabine in advanced non-small cell lung cancer. Eur J Cancer 2005:41:81-92.
[4] Marmor MD, Skaria KB, Yarden Y. Signal transduction and oncogenesis by ErbB/HER receptors Int J Radiat Oncol Biol Phys.2004;58:903-913.
[5] Kris MG Natale RB, Herbst RS, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA. 2003;290(16):2149 -2158.
[6] Grunwald V, Hidalgo M. Development of the epidermal growth factor receptor inhibitor Tarceva (OSI-774). Adv Exp Med Biol. 2003;532:235-246.
[7] Lynch, TJ, Bell, DW, Sordella, R , et al..Activating mutations in the epidermal growth factor receptor underlyingresponsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004;350, 2129-2139.
[8] Paez J G,Janne P A,Lee J C.et al.EGFR mutation in lung cancer:correlation with clicical response to gefitinib therapy.Science.2004;304:1497.
[9] Tracy S,Mukohara T,Hansen M,et al.Gefitinib induces apoptosis in EGFRL858R non-small cell lung cancer line H3255.Cancer Rec.2004;64:7241.
[10] Pao,W., Miller, V., Zakowski, et al.. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc. Natl. Acad. Sci. 2004;101,13306-13311.
[11] Han S W,Kin T Y.Hwang P Get al.Predictive and prognostic impact of epidermal growth factor receptor mutation in non-small cell cancer patients treated with gefitinib. J Clin Oncol.2005;23:l.
[12] Bianco R, Troiani T, Tortora G, et al. Intrinsic and acquired resistance to EGFR inhibitors in human cancer therapy. Endocr Relat Cancer.2005;12:S159- S171.Engelman JA, Mukohara T, Zejnullahu K, et al. A llelic dilution obscures detection of a b iologically significant resistance mutation in EGFR- amplified lung cancer.Journal of Clinical Investigation.2006;116: 2695-2706.
[13] Riely GJ, Marks J, Pao W. KRAS mutations in non-small cell lung cancer. Proc Am Thorac Soc. 2009;6:201-205.
[14] Pao, W, Wang, TY, Riely, GJ, et al. KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib. PLoS Med. 2005;2:el7.
[15] Kobayashi S, Boggon TJ, Dayaram T, et al. EGFR mutation and resistance of non-small-cell lung cancer to Gefitinib. N EngJ J Med. 2005;352:786-792.
[16] Inukai M, Toyooka S, Ito S,et al. Presence of epidermal growth factor receptor gene T790M nmtation as a nlinor clone in non-small cell lung cancer, Cancer Res.2006; 66:7854-7858.
[17] Wu SG Chang YL, Hsu YC, et al. Good response to gefitinib in lung adenocarcinoma of complex epidermal growth factor receptor (EGFR) mutations with the classical mutation pattern. Oncologist.2008;13:1276-1284.
[18] Birchmeier C, Birchmeier W, Gherardi E, et al. Met, metastasis, motility and more. Nat Rev Mol Cell Biol. 2003; 4:915-925.
[19] Ido, A. and Tsubouchi, H. Translational research to identify clinical applications of hepatocyte growth factor. Hepatol Res. 2009; 39;739-747.
[20] Giebeler, A. et al. c-Met confers protection against chronic liver tissue damage and fibrosis progression after bile duct ligation in mice.Gastroenterology.2009;137:297-308.
[21] Christensen, J. et al. c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett. 2005; 8:1-26.
[22] Liu, X. et al. Targeting the c-MET signaling pathway for cancer therapy. Expert Opin Investig Drugs. 2008; 17:997-1011.
[23] Zeng, Z.S. et al. c-Met gene amplification is associated with advanced stage colorectal cancer and liver metastases. Cancer Lett. 2008; 265:258-269.
[24] Seiwert, T.Y. et al.The MET receptor tyrosine kinase is a potential novel therapeutic target for head and neck squamous cell carcinoma. Cancer Res. 2009;69:3021-3031.
[25] Knowles, L.M. et al. HGF and c-Met participate in paracrine tumorigenic pathways in head and neck squamous cell cancer. Clin Cancer Res. 2009; 15:3740-3750.
[26] Okuda, K. et al. Met gene copy number predicts the prognosis for completely resected non-small cell lung cancer. Cancer Sci. 2008;99;2280-2285.
[27] Toiyama, Y. et al. Serum hepatocyte growth factor as a prognostic marker for stage II or III colorectal cancer patients. Int J Cancer. 2009; 125:1657-1662.
[28] Gupta, A. et al. Predictive value of plasma hepatocyte growth factor/scatter factor levels in patients with clinically localized prostate cancer. Clin Cancer Res.2008; 14:7385-7390.
[29] Cappuzzo, F. et al. Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients. J Clin Oncol. 2009;27:1667-1674.
[30] Kammula, U.S. et al. Molecular co-expression of the c-Met oncogene and hepatocyte growth factor in primary colon cancer predicts tumor stage and clinical outcome. Cancer Lett. 2007;248: 219-228.
[31] Miyata, Y. et al. Phosphorylated hepatocyte growth factor receptor/c-Met is associated with tumor growth and prognosis in patients with bladder cancer:correlation with matrix metalloproteinase-2 and -7 and E-cadherin. Hum Pathol.2009;40:496-504.
[32] Engehnan JA, Zejnullahu K, Mitsudomi T, et al. MET amplification leads to Gefitinib resistance in lung cancer by activating ERBB3 signaling. Science.2007;316:1039-1043.
[33] Engehnan JA, Mukohara T, Zejnullahu K, et al. Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. J Clin Invest. 2006;116:2695-2706.
[34] Bean J, Brennan C, Shih JY, et al. MET amplification occurs with or without T790M nlutations in EGFR mutant lung tumors with acquired resistance to Gefitinib or Erlotinib. Proc Natl Acad Sci USA. 2007;104(52):20932-20937.
[35] Engehnan JA, Janne PA, Mermel C, et al. ErbB-3 mediates phO phOinOsitide 3-kinase activity in Gefitinib. sensitive non. small cell lung cancer cell lines[J].Proc Natl Acad Sci USA. 2005; 102:3788-3793.
[36] Janmaat, ML, Kruyt, FA, Rodriguez, JA, et al. Response to epidermal growth factor receptor inhibitors in non-small cell lung cancer cells: limited antiproliferative effects and absence of apoptosis associated with persistent activity of extracellular signal-regulated kinase or Akt kinase pathways. Clin.Cancer Res. 2003; 9, 2316-2326.
[37] Vivanco, I, Sawyers, C.L. The phosphatidylinositol 3-kinase AKT pathway in human cancer. Nat. Rev. Cancer. 2002;2: 489-501.
[38] Cully,M,You, H, Levine, AJ, et al. Beyond PTEN mutations: the PI3K pathway as an integrator of multiple inputs during tumorigenesis.Nat Rev Cancer.2006;6:184-192.
[39] Bianco, R, Shin, I, Ritter, CA, et al.Loss of PTEN/MMAC1/TEP in EGF receptor-expressing tumor cells counteracts the antitumor action of EGFR tyrosine kinase inhibitors. Oncogene. 2003; 22:2812-2822.
[40] Nagata Y, Lan KH , Zhou X , et al. PTEN activation contributes to tumor inhibition by trastuzumab, and loss of PTEN predicts trastuzumab resistance in patients. Cancer Cell. 2004; 6:117-127.
[41] She QB, Solit D, Basso A, et al. Resistance to gefitinib in PTEN-null HER-overexpressing tumor cells can be overcome through restoration of PrEN function or pharmaeologie modulation of constitutive phosphatidylinositol 3 —kinase / Akt pathway signaling. Clin Cancer Res.2003; 9:4340-4346.
[42] Sos ML, Koker M, Weir BA, et al. PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR.Cancer Res. 2009 Apr 15;69:3256-3261.
[43] Samani, AA, Yakar, S, Leroith, D, et al.The Role of the IGF System in Cancer Growth and Metastasis: Overviewand Recent Insights. Endocr. Rev. 2007; 28,20-47.
[44] Takahashi, Y, Bucana, CD, Liu, W, et al.Platelet-derived endothelial cell growth factor in human colon cancer angiogenesis: role of infiltrating cells. J Natl Cancer Inst. 1996; 88: 1146-1151.
[45] Morgillo, F, Lee, HY, Resistance to epidermal growth factor receptor-targeted therapy. Drug Resist Updat. 2005; 8:298-310.
[46] Sandier AB, Johnson DH, Herbst RS. Anti-vascular endothelial growth factor monoclonals in non-small cell lung cancer. Clin Cancer Res. 2004; 10:s4258-4262.
[47] Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nat Rev Cancer. 2003;3:401-410.
[48] Viloria-Petit A, Crombet T, Jothy S, et al.Acquired resistance to the antitumor effect of epidermal growth factor receptorblocking antibodies in vivo: A role for altered tumor angiogenesis. Cancer Res. 2001;61:5090-5101.
[49] Bianco R, Rosa R, Damiano V, et al. Vascular endothelial growth factor receptor-1 contributes to resistance to anti-epidermal growth factor receptor drugs in human cancer cells. Clin Cancer Res. 2008; 14:5069-5080.
[50] Roy M. Bremnes, Carlos Camps, Rafael Sirera .Angiogenesis in non-small cell lung cancer: The prognostic impact of neoangiogenesis and the cytokines VEGF and bFGF in tumours and blood. Lung Cancer. 2006;51:143-158.
[51] Dempke WCM, Heinemann V. Resistance to EGF-R (erbB-1) and VEGF-R modulating agents. Eur J Cancer 2009;45:1117-1128.
[52] Guix M, Faber RC, Wang SE, et al. Acquired resistance to EGFR-tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. J Clin Invest.2008;118:2609-2619.
[53] Shi Z, Parmar S, Peng XX, et al. The epidermal growth factor tyrosine kinase inhibitor AG1478 and erlotinib reverse ABCG2-mediated drug resistance. Oncol Rep.2009;21:483-489.
[54] Dai CL, Tiwari AK, Wu CP, et al. Lapatinib (Tykerb,GW572016) reverses multidrug resistance in cancer cells by inhibiting the activity of ATP-binding cassette subfamily B member 1 and G member 2. Cancer Res. 2008;68:7905-7914.
[55] Johnson DH, Fehrenbacher L, Novotny WF, et al. Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol. 2004;22:2184-2191.
[56] Sandier A, Gray R, Perry MC, et al. Paclitaxelcarboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542-2550.
[57] Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for nonsquamous non-small-cell lung cancer: AVAiL. J Clin Oncol. 2009;27:1227-1234.
[58] Hainsworth J, Herbst R. A phase III multicenter, placebo-controlled, doubleblind,randomized clinical trial to evaluate the efficacy of bevacizumab (Avastin`) in combination with erlotinib (Tarceva`) compared with erlotinib alone for treatment of advanced non-small cell lung cancer after failure of standard first-line chemotherapy (BETA). J Thorac Oncol. 2008;3(Suppl. 4):S302.
[59] Laurie SA, Gauthier I, Arnold A, et al. Phase I and pharmacokinetic study of daily oral AZD2171, an inhibitor of vascular endothelial growth factor tyrosine kinases,in combination with carboplatin and paclitaxel in patients with advanced non-small-cell lung cancer: The National Cancer Institute of Canada Clinical Trials Group. J Clin Oncol. 2008;26:1871-1878.
[60] Laurie SA, Arnold A, Shepherd FA, et al. Randomizes,double-blind phase II trial of carboplatin + paclitaxel (C + P) with either daily oral cediranib, an inhibitor of vascular endothelial growth factor receptor [VEGFR] tyrosine kinases. Ann Oncol. 2009;19(Suppl. 8):90-91.
[61] Freiwald M, Liesenfeld K, Bruno R C, et al. Population pharmacokinetic analysis for BIBF 1120, an angiokinase inhibitor,in patients with advanced non-small-cell lung cancer (NSCLC). J Clin Oncol. 2008;26(Suppl.): 14528.
[62] Bahleda R, Soria J, Harbison C, et al. Tumor regression and pharmacodynamic (PD) biomarker validation in non-small cell lung cancer (NSCLC) patients treated with the ErbB/VEGFR inhibitor BMS-690514. J Clin Oncol.2009;27(Suppl.):431s.
[63] Carter, CA, Chen, C, Brink, C, et al.Sorafenib is efficacious and tolerated in combination with cytotoxic or cytostatic agents in preclinical models of human non-small cell lung carcinoma. Cancer Chemother. Pharmacol. 2007;59:183-195.
[64] Adjei, AA, Mandrekar, S, Marks, RS, et al.A Phase I study of BAY 43-9006 and gefitinib in patients with refractory or recurrent non-small-cell lung cancer (NSCLC). J. Clin. Oncol. 2005;23:3067 (abstract).
[65] Li D, Shimamura T, Ji H, et al. Bronchial and peripheral murine lung carcinomas induced by T790M-L858R mutant EGFR respond to HKI—272 and Rapamycin combination therapy. Cancer Cell. 2007; 12:81—93.
[66] Heymach JV, Johnson DH, Khuri FR, et al. Phase II study of the farnesyl transferase inhibitor R115777 in patients with sensitive relapse small cell lung cancer.Ann Oncol 2004; 15:1187-1193.
[67] Hewish M, Chau I, Cunningham D. Insulin-like growth factor 1 receptor targeted therapeutics: novel compounds and novel treatment strategies for cancer medicine.Recent Pat Anticancer Drug Discov 2009;4:54-72.
[68] Haluska P, Shaw HM, Batzel GN,et al. Phase I dose escalation trial of the anti insulin-like growth factor-I receptor monoclonal antibody CP-751,871 in patients with refractory solid tumors. Clin Cancer Res. 2007; 13:5834-5840.
[69] Lacy MQ, Alsina M, Fonseca R, et al. Phase I,pharmacokinetic and pharmacodynamic study of the anti-insulin like growth factor type 1 receptor monoclonal antibody CP-751,871 in patients with multiple myeloma. J Clin Oncol.2008;26:3196-3202.
[70] Karp DD, Paz-Ares LG, Novello S, et al. Phase II study of the anti-insulin-likegrowth factor type 1 receptor antibody CP-751,871 in combination with paclitaxel and carboplatin in previously untreated, locally advanced, or metastatic non-small-cell lung cancer. J Clin Oncol. 2009;27: 2515-2522.
[71] Han JY, Choi BG, Choi JY, et al. The prognostic significance of pretreatment plasma levels of insulin-like growth factor (IGF)-1, IGF-2, and IGF binding protein-3 in patients with advanced non-small cell lung cancer. Lung Cancer.2006;54:227-234.
[72] Kwak EL, Sordella R, Bell DW, et al. Irreversible inhibitors of the EGF receptor may cireunlvent acquired resistance to Gefitinib. Proc Natl Acad Sci USA.2005;102(21 ):7665—7670.
[73] Yang C, Hirsh V, Cadranel J, et al. Phase IIb/III doubleblind randomized trial of BIBW 2992, an irreversible, dual inhibitor of EGFR and HER2 plus best supportive care (BSC) versus placebo plus BSC in patients with NSCLC failing 1-2 lines of chemotherapy (CT) and erlotinib or gefitinib (LUX-Lung 1): a preliminary report. J Clin Oncol 2009;27(Suppl.):422s.
[74] Janne, PA. et al. Targeting MET with XL184 to reverse EGFR tyrosine kinase inhibitor (TKI) resistance in NSCLC: impact of preclinical studies on clinical trial design. European J of Cancer. 2008,Abstract 552
[75] Reardon, D.A. et al. Phase II study of AMG102, a fully human neutralizing antibody against hepatocyte growth factor/scatter factor, in patients with recurrent glioblastoma multiforme, In The ASCO Annual Meeting, 2008,Abstract 2051
[76] Ritossa, F. Discovery of the heat shock response. Cell Stress Chaperon. 1996;1:97-98.
[77] Westerheide, SD, Morimoto, RI,. Heat shock response modulators as therapeutic tools for diseases of protein conformation. J Biol Chem. 2005;280:33097- 33100.
[78] Pearl, LH, Prodromou, C, Workman, P. The Hsp90 molecular chaperone: an open and shut case for treatment. Biochem J. 2008;410:439-453.
[79] Didelot, C, Lanneau, D, Brunet, M, et al.. Anti-cancer therapeutic approaches based on intracellular and extracellular heat shock proteins. Curr Med Chem.2007; 14:2839-2847.
[80] Supko, JG, Hickman, RL, Grever, M. , et al. Preclinical pharmacologic evaluation of geldanamycin as an antitumor agent. Cancer Chemother. Pharmacol.1995;36:305-315.
[81] Bao R, Lai CJ, Wang DG, et al.Targeting heat shock protein 90 with CUDC-305 overcomes erlotinib resistance in non-small cell lung cancer Mol. Cancer Ther.,December 1, 2009; 8: 3296 - 3306.