ALK抑制剂研究进展
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摘要
间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)基因是一种跨膜受体酪氨酸激酶,可在多种恶性肿瘤中发生变异或与其他癌基因融合,是肿瘤的致癌驱动基因。ALK抑制剂包括克唑替尼、色瑞替尼及艾乐替尼,其在ALK阳性的非小细胞肺癌(non-small cell lung cancer,NSCLC)患者中已表现出显著的疗效。然而ALK抑制剂的耐药问题也较为普遍,新的抑制剂和其他靶向策略正在研发中。现对ALK抑制剂在NSCLC治疗中的研究进展及克服耐药的新策略进行综述。
As a transmembrane tyrosine kinase receptor, the anaplastic lymphoma kinase(ALK) can be oncogenically altered and fuse with other oncogenes in several malignancies. As a result, it is involved in the carcinogenesis process of cancers. ALK inhibitors, including Crizotinib, Ceritinib and Alectinib, have been demonstrated significant effectiveness in ALK-positive patients, in particular in non-small cell lung cancer(NSCLC). However, the emergence of resistance is still a concern and challenge for doctors. Newly developed ALK inhibitors and other targeting strategies are being studied. This review outlines recent developments in the treatment of ALK positive NSCLC and new strategies overcoming the ALK inhibitors resistance.
As a transmembrane tyrosine kinase receptor, the anaplastic lymphoma kinase(ALK) can be oncogenically altered and fuse with other oncogenes in several malignancies. As a result, it is involved in the carcinogenesis process of cancers. ALK inhibitors, including Crizotinib, Ceritinib and Alectinib, have been demonstrated significant effectiveness in ALK-positive patients, in particular in non-small cell lung cancer(NSCLC). However, the emergence of resistance is still a concern and challenge for doctors. Newly developed ALK inhibitors and other targeting strategies are being studied. This review outlines recent developments in the treatment of ALK positive NSCLC and new strategies overcoming the ALK inhibitors resistance.
引文
[1]Lemmon MA,Schlessinger J.Cell signaling by receptor tyrosine kinases[J].Cell,2010,141(7):1117-1134.
[2]Morris SW,Kirstein MN,Valentine MB,et al.Fusion of a kinase gene,ALK,to a nucleolar protein gene,NPM,in nonHodgkin's lymphoma[J].Science,1994,263(5151):1281-1284.
[3]Stoica GE,Kuo A,Powers C,et al.Midkine binds to anaplastic lymphoma kinase(ALK)and acts as a growth factor for different cell types[J].J Biol Chem,2002,277(39):35990-35998.
[4]Chen Z,Sasaki T,Tan X,et al.Inhibition of ALK,PI3K/MEK,and HSP90 in murine lung adenocarcinoma induced by EML4-ALK fusion oncogene[J].Cancer Res,2010,70(23):9827-9836.
[5]Bunting SF,Nussenzweig A.End-joining,translocations and cancer[J].Nat Rev Cancer,2013,13(7):443-454.
[6]Bridge JA,Kanamori M,Ma Z,et al.Fusion of the ALK gene to the clathrin heavy chain gene,CLTC,in inflammatory myofibroblastic tumor[J].Am J Pathol,2001,159(2):411-415.
[7]Damm-Welk C,Pillon M,Woessmann W,et al.Prognostic factors in paediatric anaplastic large cell lymphoma:role of ALK[J].Front Biosci(Schol Ed),2015,7(2):205-216.
[8]Soda M,Choi YL,Enomoto M,et al.Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer[J].Nature,2007,448(7153):561-566.
[9]Kwak EL,Bang YJ,Camidge DR,et al.Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer[J].N Engl J Med,2010,363(18):1693-1703.
[10]Zou HY,Friboulet L,Kodack DP,et al.PF-06463922,an ALK/ROS1 inhibitor,overcomes resistance to first and second generation ALK inhibitors in preclinical models[J].Cancer Cell,2015,28(1):70-81.
[11]Kelly LM,Barila G,Liu P,et al.Identification of the transforming STRN-ALK fusion as a potential therapeutic target in the aggressive forms of thyroid cancer[J].Proc Natl Acad Sci,2014,111(11):4233-4238.
[12]Ji JH,Oh YL,Hong M,et al.Identification of driving ALK fusion genes and genomic landscape of medullary thyroid cancer[J].PLo S Genet,2015,11(8):e1005467.
[13]Osajima-Hakomori Y,Miyake I,Ohira M,et al.Biological role of anaplastic lymphoma kinase in neuroblastoma[J].Am J Pathol,2005,167(1):213-222.
[14]Salido M,Pijuan L,Martínez-Avilés L,et al.Increased ALK gene copy number and amplification are frequent in non-small cell lung cancer[J].J Thorac Oncol,2011,6(1):21-27.
[15]Schoppmann SF,Streubel B,Birner P.Amplification but not translocation of anaplastic lymphoma kinase is a frequent event in oesophageal cancer[J].Eur J Cancer,2013,49(8):1876-1881.
[16]Pietrantonio F,Maggi C,Di Bartolomeo M,et al.Gain of ALK gene copy number may predict lack of benefit from antiEGFR treatment in patients with advanced colorectal cancer and RAS-RAF-PI3KCA wild-type status[J].PLo S One,2014,9(4):e92147.
[17]Siraj AK,Beg S,Jehan Z,et al.ALK alteration is a frequent event in aggressive breast cancers[J].Breast Cancer Res,2015,17:127.
[18]Lee JS,Lim SM,Rha SY,et al.Prognostic implications of anaplastic lymphoma kinase gene aberrations in rhabdomyosarcoma;an immunohistochemical and fluorescence in situ hybrid isation study[J].J Clin Pathol,2014,67(1):33-39.
[19]Camidge DR,Bang YJ,Kwak EL,et al.Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer:updated results from a phaseⅠstudy[J].Lancet Oncol,2012,13(10):1011-1019.
[20]Shaw AT,Kim DW,Nakagawa K,et al.Crizotinib versus chemotherapy in advanced ALK-positive lung cancer[J].N Engl J Med,2013,368(25):2385-2394.
[21]Solomon BJ,Mok T,Kim DW,et al.First-line crizotinib versus chemotherapy in ALK-positive lung cancer[J].N Engl J Med,2014,371(23):2167-2177.
[22]Butrynski JE,D'Adamo DR,Hornick JL,et al.Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor[J].N Engl J Med,2010,363(18):1727-1733.
[23]MosséYP,Lim MS,Voss SD,et al.Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma:a Children's oncology group phaseⅠconsortium study[J].Lancet Oncol,2013,14(6):472-480.
[24]Choi YL,Soda M,Yamashita Y,et al.EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors[J].N Engl J Med,2010,363(18):1734-1739.
[25]Sasaki T,Okuda K,Zheng W,et al.The neuroblastomaassociated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers[J].Cancer Res,2010,70(24):10038-10043.
[26]Doebele RC,Pilling AB,Aisner DL,et al.Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer[J].Clin Cancer Res,2012,18(5):1472-1482.
[27]Katayama R,Shaw AT,Khan TM,et al.Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers[J].Sci Transl Med,2012,4(120):120ra17.
[28]Friboulet L,Li N,Katayama R,et al.The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer[J].Cancer Discov,2014,4(6):662-673.
[29]Shaw AT,Spigel DR,Tan DS,et al.MINI01.01:whole body and intracranial efficacy of ceritinib in ALK-inhibitor na?ve patients with ALK NSCLC and brain metastases:results of ASCEND 1 and 3:topic:medical oncology[J].J Thorac Oncol,2016,11(11S):S256.
[30]CrinòL,Ahn MJ,De Marinis F,et al.Multicenter phaseⅡstudy of whole-body and intracranial activity with ceritinib in patients with ALK-rearranged non-small-cell lung cancer previously treated with chemotherapy and crizotinib:results from ASCEND-2[J].J Clin Oncol,2016,34(24):2866-2873.
[31]Soria JC,Tan DSW,Chiari R,et al.First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer(ASCEND-4):a randomised,openlabel,phaseⅢstudy[J].Lancet,2017,389(10072):917-929.
[32]Kodama T,Tsukaguchi T,Yoshida M,et al.Selective ALK inhibitor alectinib with potent antitumor activity in models of crizotinib resistance[J].Cancer Lett,2014,351(2):215-221.
[33]Larkins E,Blumenthal GM,Chen H,et al.FDA approval:alectinib for the treatment of metastatic,ALK-positive nonsmall cell lung cancer following crizotinib[J].Clin Cancer Res,2016,22(21):5171-5176.
[34]Seto T,Kiura K,Nishio M,et al.CH5424802(RO5424802)for patients with ALK-rearranged advanced nonsmall-cell lung cancer(AF-001JP study):a single-arm,open-label,phase 1-2study[J].Lancet Oncol,2013,14(7):590-598.
[35]Gadgeel SM,Gandhi L,Riely GJ,et al.Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged nonsmall-cell lung cancer(AF-002JG):results from the dosefinding portion of a phase 1/2 study[J].Lancet Oncol,2014,15(10):1119-1128.
[36]Shaw AT,Gandhi L,Gadgeel S,et al.Alectinib in ALKpositive,crizotinib-resistant,non-small-cell lung cancer:a single-group,multi-centre,phaseⅡtrial[J].Lancet Oncol,2016,17(2):234-242.
[37]Ou SH,Ahn JS,De Petris L,et al.Alectinib in crizotinibrefractory ALK-rearranged non-small-cell lung cancer:a phaseⅡglobal study[J].J Clin Oncol,2016,34(7):661-668.
[38]Kodama T,Hasegawa M,Takanashi K,et al.Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases[J].Cancer Chemother Pharmacol,2014,74(5):1023-1028.
[39]Hida T,Nokihara H,Kondo M,et al.Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer(J-ALEX):an open-label,randomised phase 3 trial[J].Lancet,2017,390(10089):29-39.
[40]Peters S,Camidge DR,Shaw AT,et al.Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer[J].N Engl J Med,2017,377(9):829-838.
[41]Markham A.Brigatinib:first global approval[J].Drugs,2017,77(10):1131-1135.
[42]Menichincheri M,Ardini E,Magnaghi P,et al.Discovery of Entrectinib:a new 3-Aminoindazole as a potent anaplastic lymphoma kinase(ALK),c-ROS oncogene 1 kinase(ROS1),and pantropomyosin receptor kinases(pan-TRKs)inhibitor[J].J Med Chem,2016,59(7):3392-3408.
[43]Drilon A,Siena S,Ou SI,et al.Safety and antitumor activity of the multitargeted pan-TRK,ROS1,and ALK inhibitor Entrectinib:combined results from two phaseⅠtrials(ALKA-372-001 and STARTRK-1)[J].Cancer Discov,2017,7(4):400-409.
[44]Shaw AT,Felip E,Bauer TM,et al.Lorlatinib in non-smallcell lung cancer with ALK or ROS1 rearrangement:an international,multicentre,open-label,single-arm first-in-man phase 1 trial[J].Lancet Oncol,2017,18(12):1590-1599.
[45]Sang J,Acquaviva J,Friedland JC,et al.Targeted inhibition of the molecular chaperone Hsp90 overcomes ALK inhibitor resistance in non-small cell lung cancer[J].Cancer Discov,2013,3(4):430-443.
[46]Lovly CM,Mc Donald NT,Chen H,et al.Rationale for cotargeting IGF-1R and ALK in ALK fusion-positive lung cancer[J].Nat Med,2014,20(9):1027-1034.
[47]Tanizaki J,Okamoto I,Takezawa K,et al.Combined effect of ALK and MEK inhibitors in EML4-ALK-positive non-small cell lung cancer cells[J].Br J Cancer,2012,106(4):763-767.
[2]Morris SW,Kirstein MN,Valentine MB,et al.Fusion of a kinase gene,ALK,to a nucleolar protein gene,NPM,in nonHodgkin's lymphoma[J].Science,1994,263(5151):1281-1284.
[3]Stoica GE,Kuo A,Powers C,et al.Midkine binds to anaplastic lymphoma kinase(ALK)and acts as a growth factor for different cell types[J].J Biol Chem,2002,277(39):35990-35998.
[4]Chen Z,Sasaki T,Tan X,et al.Inhibition of ALK,PI3K/MEK,and HSP90 in murine lung adenocarcinoma induced by EML4-ALK fusion oncogene[J].Cancer Res,2010,70(23):9827-9836.
[5]Bunting SF,Nussenzweig A.End-joining,translocations and cancer[J].Nat Rev Cancer,2013,13(7):443-454.
[6]Bridge JA,Kanamori M,Ma Z,et al.Fusion of the ALK gene to the clathrin heavy chain gene,CLTC,in inflammatory myofibroblastic tumor[J].Am J Pathol,2001,159(2):411-415.
[7]Damm-Welk C,Pillon M,Woessmann W,et al.Prognostic factors in paediatric anaplastic large cell lymphoma:role of ALK[J].Front Biosci(Schol Ed),2015,7(2):205-216.
[8]Soda M,Choi YL,Enomoto M,et al.Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer[J].Nature,2007,448(7153):561-566.
[9]Kwak EL,Bang YJ,Camidge DR,et al.Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer[J].N Engl J Med,2010,363(18):1693-1703.
[10]Zou HY,Friboulet L,Kodack DP,et al.PF-06463922,an ALK/ROS1 inhibitor,overcomes resistance to first and second generation ALK inhibitors in preclinical models[J].Cancer Cell,2015,28(1):70-81.
[11]Kelly LM,Barila G,Liu P,et al.Identification of the transforming STRN-ALK fusion as a potential therapeutic target in the aggressive forms of thyroid cancer[J].Proc Natl Acad Sci,2014,111(11):4233-4238.
[12]Ji JH,Oh YL,Hong M,et al.Identification of driving ALK fusion genes and genomic landscape of medullary thyroid cancer[J].PLo S Genet,2015,11(8):e1005467.
[13]Osajima-Hakomori Y,Miyake I,Ohira M,et al.Biological role of anaplastic lymphoma kinase in neuroblastoma[J].Am J Pathol,2005,167(1):213-222.
[14]Salido M,Pijuan L,Martínez-Avilés L,et al.Increased ALK gene copy number and amplification are frequent in non-small cell lung cancer[J].J Thorac Oncol,2011,6(1):21-27.
[15]Schoppmann SF,Streubel B,Birner P.Amplification but not translocation of anaplastic lymphoma kinase is a frequent event in oesophageal cancer[J].Eur J Cancer,2013,49(8):1876-1881.
[16]Pietrantonio F,Maggi C,Di Bartolomeo M,et al.Gain of ALK gene copy number may predict lack of benefit from antiEGFR treatment in patients with advanced colorectal cancer and RAS-RAF-PI3KCA wild-type status[J].PLo S One,2014,9(4):e92147.
[17]Siraj AK,Beg S,Jehan Z,et al.ALK alteration is a frequent event in aggressive breast cancers[J].Breast Cancer Res,2015,17:127.
[18]Lee JS,Lim SM,Rha SY,et al.Prognostic implications of anaplastic lymphoma kinase gene aberrations in rhabdomyosarcoma;an immunohistochemical and fluorescence in situ hybrid isation study[J].J Clin Pathol,2014,67(1):33-39.
[19]Camidge DR,Bang YJ,Kwak EL,et al.Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer:updated results from a phaseⅠstudy[J].Lancet Oncol,2012,13(10):1011-1019.
[20]Shaw AT,Kim DW,Nakagawa K,et al.Crizotinib versus chemotherapy in advanced ALK-positive lung cancer[J].N Engl J Med,2013,368(25):2385-2394.
[21]Solomon BJ,Mok T,Kim DW,et al.First-line crizotinib versus chemotherapy in ALK-positive lung cancer[J].N Engl J Med,2014,371(23):2167-2177.
[22]Butrynski JE,D'Adamo DR,Hornick JL,et al.Crizotinib in ALK-rearranged inflammatory myofibroblastic tumor[J].N Engl J Med,2010,363(18):1727-1733.
[23]MosséYP,Lim MS,Voss SD,et al.Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma:a Children's oncology group phaseⅠconsortium study[J].Lancet Oncol,2013,14(6):472-480.
[24]Choi YL,Soda M,Yamashita Y,et al.EML4-ALK mutations in lung cancer that confer resistance to ALK inhibitors[J].N Engl J Med,2010,363(18):1734-1739.
[25]Sasaki T,Okuda K,Zheng W,et al.The neuroblastomaassociated F1174L ALK mutation causes resistance to an ALK kinase inhibitor in ALK-translocated cancers[J].Cancer Res,2010,70(24):10038-10043.
[26]Doebele RC,Pilling AB,Aisner DL,et al.Mechanisms of resistance to crizotinib in patients with ALK gene rearranged non-small cell lung cancer[J].Clin Cancer Res,2012,18(5):1472-1482.
[27]Katayama R,Shaw AT,Khan TM,et al.Mechanisms of acquired crizotinib resistance in ALK-rearranged lung cancers[J].Sci Transl Med,2012,4(120):120ra17.
[28]Friboulet L,Li N,Katayama R,et al.The ALK inhibitor ceritinib overcomes crizotinib resistance in non-small cell lung cancer[J].Cancer Discov,2014,4(6):662-673.
[29]Shaw AT,Spigel DR,Tan DS,et al.MINI01.01:whole body and intracranial efficacy of ceritinib in ALK-inhibitor na?ve patients with ALK NSCLC and brain metastases:results of ASCEND 1 and 3:topic:medical oncology[J].J Thorac Oncol,2016,11(11S):S256.
[30]CrinòL,Ahn MJ,De Marinis F,et al.Multicenter phaseⅡstudy of whole-body and intracranial activity with ceritinib in patients with ALK-rearranged non-small-cell lung cancer previously treated with chemotherapy and crizotinib:results from ASCEND-2[J].J Clin Oncol,2016,34(24):2866-2873.
[31]Soria JC,Tan DSW,Chiari R,et al.First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer(ASCEND-4):a randomised,openlabel,phaseⅢstudy[J].Lancet,2017,389(10072):917-929.
[32]Kodama T,Tsukaguchi T,Yoshida M,et al.Selective ALK inhibitor alectinib with potent antitumor activity in models of crizotinib resistance[J].Cancer Lett,2014,351(2):215-221.
[33]Larkins E,Blumenthal GM,Chen H,et al.FDA approval:alectinib for the treatment of metastatic,ALK-positive nonsmall cell lung cancer following crizotinib[J].Clin Cancer Res,2016,22(21):5171-5176.
[34]Seto T,Kiura K,Nishio M,et al.CH5424802(RO5424802)for patients with ALK-rearranged advanced nonsmall-cell lung cancer(AF-001JP study):a single-arm,open-label,phase 1-2study[J].Lancet Oncol,2013,14(7):590-598.
[35]Gadgeel SM,Gandhi L,Riely GJ,et al.Safety and activity of alectinib against systemic disease and brain metastases in patients with crizotinib-resistant ALK-rearranged nonsmall-cell lung cancer(AF-002JG):results from the dosefinding portion of a phase 1/2 study[J].Lancet Oncol,2014,15(10):1119-1128.
[36]Shaw AT,Gandhi L,Gadgeel S,et al.Alectinib in ALKpositive,crizotinib-resistant,non-small-cell lung cancer:a single-group,multi-centre,phaseⅡtrial[J].Lancet Oncol,2016,17(2):234-242.
[37]Ou SH,Ahn JS,De Petris L,et al.Alectinib in crizotinibrefractory ALK-rearranged non-small-cell lung cancer:a phaseⅡglobal study[J].J Clin Oncol,2016,34(7):661-668.
[38]Kodama T,Hasegawa M,Takanashi K,et al.Antitumor activity of the selective ALK inhibitor alectinib in models of intracranial metastases[J].Cancer Chemother Pharmacol,2014,74(5):1023-1028.
[39]Hida T,Nokihara H,Kondo M,et al.Alectinib versus crizotinib in patients with ALK-positive non-small-cell lung cancer(J-ALEX):an open-label,randomised phase 3 trial[J].Lancet,2017,390(10089):29-39.
[40]Peters S,Camidge DR,Shaw AT,et al.Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer[J].N Engl J Med,2017,377(9):829-838.
[41]Markham A.Brigatinib:first global approval[J].Drugs,2017,77(10):1131-1135.
[42]Menichincheri M,Ardini E,Magnaghi P,et al.Discovery of Entrectinib:a new 3-Aminoindazole as a potent anaplastic lymphoma kinase(ALK),c-ROS oncogene 1 kinase(ROS1),and pantropomyosin receptor kinases(pan-TRKs)inhibitor[J].J Med Chem,2016,59(7):3392-3408.
[43]Drilon A,Siena S,Ou SI,et al.Safety and antitumor activity of the multitargeted pan-TRK,ROS1,and ALK inhibitor Entrectinib:combined results from two phaseⅠtrials(ALKA-372-001 and STARTRK-1)[J].Cancer Discov,2017,7(4):400-409.
[44]Shaw AT,Felip E,Bauer TM,et al.Lorlatinib in non-smallcell lung cancer with ALK or ROS1 rearrangement:an international,multicentre,open-label,single-arm first-in-man phase 1 trial[J].Lancet Oncol,2017,18(12):1590-1599.
[45]Sang J,Acquaviva J,Friedland JC,et al.Targeted inhibition of the molecular chaperone Hsp90 overcomes ALK inhibitor resistance in non-small cell lung cancer[J].Cancer Discov,2013,3(4):430-443.
[46]Lovly CM,Mc Donald NT,Chen H,et al.Rationale for cotargeting IGF-1R and ALK in ALK fusion-positive lung cancer[J].Nat Med,2014,20(9):1027-1034.
[47]Tanizaki J,Okamoto I,Takezawa K,et al.Combined effect of ALK and MEK inhibitors in EML4-ALK-positive non-small cell lung cancer cells[J].Br J Cancer,2012,106(4):763-767.