PI3K/Akt/mTOR信号通路在三阴性乳腺癌治疗中的研究进展
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摘要
三阴性乳腺癌是乳腺癌中的一种特殊分型,异质性强,有效作用靶点不明,具有侵袭早,转移快,预后差等特点,5年生存率低,是乳腺癌中病死率最高的一种亚型。目前已对一些潜在的分子靶点做了一些实验,但一些研究发现,PI3K/Akt/mTOR信号通路抑制剂对于三阴性乳腺癌的抑制作用更为明显,一些抑制剂已经进入了预试验或早期临床试验阶段。该文主要介绍三阴性乳腺癌的分子分型,PI3K/Akt/mTOR信号传导通路的异常激活机制及所涉及的关键基因在三阴性乳腺癌中的表达水平和相关抑制剂的治疗加以综述,以期为该类型的乳腺癌提供更好的治疗途径。
Triple negative breast cancer(TNBC)is a special subtype of breast carcinoma,characterized by highly invasiveness,early metastasis and poor prognosis due to its heterogeneity and lack of effective target.Recent studies have demonstrated some potential molecular targets in TNBC.The inhibitors of PI3K/Akt/mTOR pathway showed a significant effect on TNBC,and preclinical development or early phase clinical trials of several PI3K/Akt/mTOR inhibitors are on the way.This article reviews the molecular typing of TNBC,the current researches on the mechanism of abnormal activation of PI3K/Akt/mTOR signaling pathway and its related key genes,and also the effects of its inhibitors;hopefully it may offer new approach for the treatment of TNBC.
Triple negative breast cancer(TNBC)is a special subtype of breast carcinoma,characterized by highly invasiveness,early metastasis and poor prognosis due to its heterogeneity and lack of effective target.Recent studies have demonstrated some potential molecular targets in TNBC.The inhibitors of PI3K/Akt/mTOR pathway showed a significant effect on TNBC,and preclinical development or early phase clinical trials of several PI3K/Akt/mTOR inhibitors are on the way.This article reviews the molecular typing of TNBC,the current researches on the mechanism of abnormal activation of PI3K/Akt/mTOR signaling pathway and its related key genes,and also the effects of its inhibitors;hopefully it may offer new approach for the treatment of TNBC.
引文
[1]Gelmon K,Dent R,Mackey JR,et al.Targeting triple-negative breast cancer:optimising therapeutic outcomes[J].Ann Oncol,2012,23(9):2223-2234.
[2]Liedtke C,Rody A,Gluz O.The prognostic impact of age in different molecular subtypes of breast cancer[J].Breast Cancer Res Treat,2015,152(3):667-673.
[3]Cinkaya A,Akin M,Sengul A.Evaluation of treatment outcomes of triple-negative breast cancer[J].J Cancer Res Ther,2016,12(12 1):150-154.
[4]Toss A,Cristofanilli M.Molecular characterization and targeted therapeutic approaches in breast cancer[J].Breast Cancer Res,2015,17(1):60.
[5]Bauer JA,Chakravarthy AB,Rosenbluth JM,et al.Identification of markers of taxane sensitivity using proteomic and genomic analyses of breast tumors from patients receiving neoadjuvant paclitaxel and radiation[J].Clin Cancer Res,2010,16(16):681-690.
[6]Lehmann BD,Bauer JA,Chen X,et al.Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies[J].J Clin Invest,2011,121(7):2750.
[7]Barton VN,D’Amato NC,Gordon MA,et al.Multiple molecular subtypes of triple-negative breast cancer critically rely on androgen receptor and respond to enzalutamide in vivo[J].Mol Cancer Ther 2015,14(3):769.
[8]Wu Q,Zhao QN,Song WD.The research and progress of PI3K/Akt/m TOR signal transduction pathway in tumors[J].Journal of Diseases Monitor&Control,2013,7(6):346-347.[武强,赵全年,宋卫东.PI3K/Akt/m TOR信号传导通路在肿瘤的研究进展[J].疾病监测与控制,2013,7(6):346-347.]
[9]Massihnia D,Perez A,Bazan V,et al.A headlight on liquid biopsies:a challenging tool for breast cancer management[J].Tumor Biol,2016,37(4):4263-4273.
[10]Yentrapalli R,Azimzadeh O,Sriharshan A,et al.The PI3K/Akt/m TOR pathway is implicated in the premature senescence of primary human endothelial cells exposed to chronic radiation[J].PLo S One,2013,8(8):e70024.
[11]Jing T,Qiang Y.Molecular mechanisms of tumor resistance to PI3K-m TOR-targeted therapy[J].Chin J Cancer,2013,32(7):376.
[12]Chen L,Cui GZ,Yang M,et al.Protein expressions and significances of PTEN in triple-negative breast cancer and non-triple-negative breast cancer[J].Modern Journal of Integrated Traditional Chinese and Western Medicine,2014,23(36):4013-4015.[陈亮,崔国忠,杨猛,等.抑癌基因PTEN在三阴性乳腺癌及非三阴性乳腺癌中的表达及临床意义[J].现代中西医结合杂志,2014,23(36):4013-4015.]
[13]Shinobu U,Sei Y,Yoshikazu O,et al.Increased phosphorylation of Akt in triple negative breast cancers[J].Cancer Sci,2007,98(12):1889.
[14]Walsh S,Flanagan L,Quinn C,et al.m TOR in breast cancer:differential expression in triple-negative and nontriple-negative tumors[J].Breast,2012,21(21):178-182.
[15]Ueng SH,Chen SC,Chang YS,et al.Phosphorylated m TOR expression correlates with poor outcome in earlystage triple negative breast carcinomas.[J].Int J Clin Exp Pathol,2012,5(8):806-813.
[16]Liu P,Cheng H,Roberts TM,et al.Targeting the phosphoinositide 3-kinase pathway in cancer.[J].Nat Rev Drug Discov,2009,8(8):627-644.
[17]Vanhaesebroeck B,Guillermet-Guibert J,Graupera M,et al.The emerging mechanisms of isoform-specific PI3K signalling[J].Nat Rev Mol Cell Biol,2010,11(11):329-341.
[18]Deng M,Wang J,Chen Y,et al.Combination of SF1126and gefitinib induces apoptosis of triple-negative breast cancer cells through the PI3K/AKT-m TOR pathway[J].Anti-cancer drugs,2015,26(4):422.
[19]Tang XF,Jang LH,Zeng FX,et al.Effects of phosphoinositide 3-kinase inhibitor on the proliferation and migration of triple-negative breast cancer cell lines[J].Journal of Chongqing Medical University,2013,5:478-482.[唐小飞,姜立花,曾凡新,等.磷酯酰肌醇3激酶抑制剂对三阴性乳腺癌细胞增殖及迁移的影响[J].重庆医科大学学报,2013,5:478-482.]
[20]Lin SY,Zhang LH,Li XD.The reversal effect of PI3K inhibitor on multidrug-resistant triple negative human breast cancer cell line MEDA-MB-231/ADR[J].Journal of Clinical and Experimental Medicine,2015,1:1-4.[林思园,张利华,李想娣.PI3K抑制剂对三阴性人乳腺癌细胞株MBA-MB-231/ADR的多药耐药逆转作用[J].临床和实验医学杂志,2015,1:1-4.]
[21]De P,Sun Y,Carlson JH,et al.Doubling down on the PI3K-AKT-m TOR pathway enhances the antitumor efficacy of PARP inhibitor in triple negative breast cancer model beyond BRCA-ness[J].Neoplasia,2014,16(1):43-72.
[22]Nandini D,Pradip D,Brian LJ.PI3K-AKT-m TOR inhibitors in breast cancers:from tumor cell signaling to clinical trials[J].Pharmacol Ther,2017.[Epub ahead of print]
[23]Lopiccolo J,Blumenthal GM,Bernstein WB,et al.Targeting the PI3K/Akt/m TOR pathway:effective combinations and clinical considerations[J].Drug Resist Updat,2008,11(1-2):32-50.
[24]Chin YR,Yoshida T,Marusyk A,et al.Targeting AKT3signaling in triple negative breast cancer[J].Cancer Res,2013,74(3):964-973.
[25]Tripathy D,Chien AJ,Hylton N,et al.Adaptively randomized trial of neoadjuvant chemotherapy with or without the Akt inhibitor MK-2206:graduation results from the I-SPY2 trial[J].J Clin Oncol,2015,33(15 Suppl):524.
[26]Wan X,Helman LJ.The biology behind m TOR inhibition in sarcoma[J].Oncologist,2007,12(8):1007-1018.
[27]Zhang H,Cohen AL,Krishnakumar S,et al.Patient-derived xenografts of triple-negative breast cancer reproduce molecular features of patient tumors and respond to m TOR inhibition[J].Breast Cancer Res,2014,16(2):R36.
[28]Tomao F,Papa A,Zaccarelli E,et al.Triple-negative breast cancer:new perspectives for targeted therapies[J].Onco Targets Ther,2015,8:177-193.
[29]Dai W,Yang F,Ma L,et al.Combined m TOR inhibitor rapamycin and doxorubicin-loaded cyclicoctapeptide modified liposomes for targeting integrinα3 in triple-negative breast cancer[J].Biomaterials,2014,35(20):5347-5358.
[30]Khotskaya YB,Goverdhan A,Shen J,et al.S6K1 promotes invasiveness of breast cancer cells in a model of metastasis of triple-negative breast cancer[J].Am J Transl Res,2014,6(6):361-376.
[31]Shrivastava S,Jeengar MK,Reddy VS,et al.Anticancer effect of celastrol on human triple negative breast cancer:possible involvement of oxidative stress,mitochondrial dysfunction,apoptosis and PI3K/Akt pathways[J].Exp Mol Pathol,2015,98(3):313-327.
[32]Lehmann BD,Bauer JA,Schafer JM,et al.PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors[J].Breast Cancer Res,2014,16(4):406.
[33]Chirumbolo S.Quercetin in cancer prevention and therapy[J].Integr Cancer Ther,2013,12(2):97.
[34]Cai PT,Wu ZQ,Guo H,et al.Research progress on Chinese material medica in overcoming EGFR-TKIs acquired drugs resistance through PI3K/Akt/m TOR pathway[J].Chinese Traditional and Herbal Drugs,2015,46(12):1849-1852.[蔡鹏涛,吴志强,郭会,等.中药抑制非小细胞肺癌PI3K/Akt/m TOR信号通路克服EGFR-TKIs获得性耐药研究进展[J].中草药,2015,46(12):1849-1852.]
[35]Paplomata E,O’Regan R.The PI3K/AKT/m TOR pathway in breast cancer:targets,trials and biomarkers[J].Ther Adv Med Oncol,2014,6(4):154-166.
[36]Kim HI,Huang H,Cheepala S,et al.Curcumin inhibition of integrin(alpha6beta4)-dependent breast cancer cell motility and invasion[J].Cancer Prev Res,2008,1(5):385.
[37]Ye MN,Chen HF,Zhou RJ,et al.Effects of astragalus polysaccharide on proliferation and Akt phosphorylation of the basal-like breast cancer cell line[J].Journal of Chinese Integrative Medicine,2011,9(12):1339-1346.[叶媚娜,陈红风,周瑞娟,等.黄芪多糖对基底细胞样乳腺癌细胞增殖和Akt磷酸化的影响[J].中西医结合医学学报,2011,9(12):1339-1346.]
[38]Liao MJ,Ye MN,Zhou RJ,et al.Yiqi formula enhances the antitumor effects of erlotinib for treatment of triplenegative breast cancer xenografts.[J].Evid-Based Compl Alt,2013,2014(2):628712.
[39]Massihnia D,Galvano A,Fanale D,et al.Triple negative breast cancer:shedding light onto the role of PI3K/Akt/m TOR pathway[J].Oncotarget,2016,7(37):60712.
[2]Liedtke C,Rody A,Gluz O.The prognostic impact of age in different molecular subtypes of breast cancer[J].Breast Cancer Res Treat,2015,152(3):667-673.
[3]Cinkaya A,Akin M,Sengul A.Evaluation of treatment outcomes of triple-negative breast cancer[J].J Cancer Res Ther,2016,12(12 1):150-154.
[4]Toss A,Cristofanilli M.Molecular characterization and targeted therapeutic approaches in breast cancer[J].Breast Cancer Res,2015,17(1):60.
[5]Bauer JA,Chakravarthy AB,Rosenbluth JM,et al.Identification of markers of taxane sensitivity using proteomic and genomic analyses of breast tumors from patients receiving neoadjuvant paclitaxel and radiation[J].Clin Cancer Res,2010,16(16):681-690.
[6]Lehmann BD,Bauer JA,Chen X,et al.Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies[J].J Clin Invest,2011,121(7):2750.
[7]Barton VN,D’Amato NC,Gordon MA,et al.Multiple molecular subtypes of triple-negative breast cancer critically rely on androgen receptor and respond to enzalutamide in vivo[J].Mol Cancer Ther 2015,14(3):769.
[8]Wu Q,Zhao QN,Song WD.The research and progress of PI3K/Akt/m TOR signal transduction pathway in tumors[J].Journal of Diseases Monitor&Control,2013,7(6):346-347.[武强,赵全年,宋卫东.PI3K/Akt/m TOR信号传导通路在肿瘤的研究进展[J].疾病监测与控制,2013,7(6):346-347.]
[9]Massihnia D,Perez A,Bazan V,et al.A headlight on liquid biopsies:a challenging tool for breast cancer management[J].Tumor Biol,2016,37(4):4263-4273.
[10]Yentrapalli R,Azimzadeh O,Sriharshan A,et al.The PI3K/Akt/m TOR pathway is implicated in the premature senescence of primary human endothelial cells exposed to chronic radiation[J].PLo S One,2013,8(8):e70024.
[11]Jing T,Qiang Y.Molecular mechanisms of tumor resistance to PI3K-m TOR-targeted therapy[J].Chin J Cancer,2013,32(7):376.
[12]Chen L,Cui GZ,Yang M,et al.Protein expressions and significances of PTEN in triple-negative breast cancer and non-triple-negative breast cancer[J].Modern Journal of Integrated Traditional Chinese and Western Medicine,2014,23(36):4013-4015.[陈亮,崔国忠,杨猛,等.抑癌基因PTEN在三阴性乳腺癌及非三阴性乳腺癌中的表达及临床意义[J].现代中西医结合杂志,2014,23(36):4013-4015.]
[13]Shinobu U,Sei Y,Yoshikazu O,et al.Increased phosphorylation of Akt in triple negative breast cancers[J].Cancer Sci,2007,98(12):1889.
[14]Walsh S,Flanagan L,Quinn C,et al.m TOR in breast cancer:differential expression in triple-negative and nontriple-negative tumors[J].Breast,2012,21(21):178-182.
[15]Ueng SH,Chen SC,Chang YS,et al.Phosphorylated m TOR expression correlates with poor outcome in earlystage triple negative breast carcinomas.[J].Int J Clin Exp Pathol,2012,5(8):806-813.
[16]Liu P,Cheng H,Roberts TM,et al.Targeting the phosphoinositide 3-kinase pathway in cancer.[J].Nat Rev Drug Discov,2009,8(8):627-644.
[17]Vanhaesebroeck B,Guillermet-Guibert J,Graupera M,et al.The emerging mechanisms of isoform-specific PI3K signalling[J].Nat Rev Mol Cell Biol,2010,11(11):329-341.
[18]Deng M,Wang J,Chen Y,et al.Combination of SF1126and gefitinib induces apoptosis of triple-negative breast cancer cells through the PI3K/AKT-m TOR pathway[J].Anti-cancer drugs,2015,26(4):422.
[19]Tang XF,Jang LH,Zeng FX,et al.Effects of phosphoinositide 3-kinase inhibitor on the proliferation and migration of triple-negative breast cancer cell lines[J].Journal of Chongqing Medical University,2013,5:478-482.[唐小飞,姜立花,曾凡新,等.磷酯酰肌醇3激酶抑制剂对三阴性乳腺癌细胞增殖及迁移的影响[J].重庆医科大学学报,2013,5:478-482.]
[20]Lin SY,Zhang LH,Li XD.The reversal effect of PI3K inhibitor on multidrug-resistant triple negative human breast cancer cell line MEDA-MB-231/ADR[J].Journal of Clinical and Experimental Medicine,2015,1:1-4.[林思园,张利华,李想娣.PI3K抑制剂对三阴性人乳腺癌细胞株MBA-MB-231/ADR的多药耐药逆转作用[J].临床和实验医学杂志,2015,1:1-4.]
[21]De P,Sun Y,Carlson JH,et al.Doubling down on the PI3K-AKT-m TOR pathway enhances the antitumor efficacy of PARP inhibitor in triple negative breast cancer model beyond BRCA-ness[J].Neoplasia,2014,16(1):43-72.
[22]Nandini D,Pradip D,Brian LJ.PI3K-AKT-m TOR inhibitors in breast cancers:from tumor cell signaling to clinical trials[J].Pharmacol Ther,2017.[Epub ahead of print]
[23]Lopiccolo J,Blumenthal GM,Bernstein WB,et al.Targeting the PI3K/Akt/m TOR pathway:effective combinations and clinical considerations[J].Drug Resist Updat,2008,11(1-2):32-50.
[24]Chin YR,Yoshida T,Marusyk A,et al.Targeting AKT3signaling in triple negative breast cancer[J].Cancer Res,2013,74(3):964-973.
[25]Tripathy D,Chien AJ,Hylton N,et al.Adaptively randomized trial of neoadjuvant chemotherapy with or without the Akt inhibitor MK-2206:graduation results from the I-SPY2 trial[J].J Clin Oncol,2015,33(15 Suppl):524.
[26]Wan X,Helman LJ.The biology behind m TOR inhibition in sarcoma[J].Oncologist,2007,12(8):1007-1018.
[27]Zhang H,Cohen AL,Krishnakumar S,et al.Patient-derived xenografts of triple-negative breast cancer reproduce molecular features of patient tumors and respond to m TOR inhibition[J].Breast Cancer Res,2014,16(2):R36.
[28]Tomao F,Papa A,Zaccarelli E,et al.Triple-negative breast cancer:new perspectives for targeted therapies[J].Onco Targets Ther,2015,8:177-193.
[29]Dai W,Yang F,Ma L,et al.Combined m TOR inhibitor rapamycin and doxorubicin-loaded cyclicoctapeptide modified liposomes for targeting integrinα3 in triple-negative breast cancer[J].Biomaterials,2014,35(20):5347-5358.
[30]Khotskaya YB,Goverdhan A,Shen J,et al.S6K1 promotes invasiveness of breast cancer cells in a model of metastasis of triple-negative breast cancer[J].Am J Transl Res,2014,6(6):361-376.
[31]Shrivastava S,Jeengar MK,Reddy VS,et al.Anticancer effect of celastrol on human triple negative breast cancer:possible involvement of oxidative stress,mitochondrial dysfunction,apoptosis and PI3K/Akt pathways[J].Exp Mol Pathol,2015,98(3):313-327.
[32]Lehmann BD,Bauer JA,Schafer JM,et al.PIK3CA mutations in androgen receptor-positive triple negative breast cancer confer sensitivity to the combination of PI3K and androgen receptor inhibitors[J].Breast Cancer Res,2014,16(4):406.
[33]Chirumbolo S.Quercetin in cancer prevention and therapy[J].Integr Cancer Ther,2013,12(2):97.
[34]Cai PT,Wu ZQ,Guo H,et al.Research progress on Chinese material medica in overcoming EGFR-TKIs acquired drugs resistance through PI3K/Akt/m TOR pathway[J].Chinese Traditional and Herbal Drugs,2015,46(12):1849-1852.[蔡鹏涛,吴志强,郭会,等.中药抑制非小细胞肺癌PI3K/Akt/m TOR信号通路克服EGFR-TKIs获得性耐药研究进展[J].中草药,2015,46(12):1849-1852.]
[35]Paplomata E,O’Regan R.The PI3K/AKT/m TOR pathway in breast cancer:targets,trials and biomarkers[J].Ther Adv Med Oncol,2014,6(4):154-166.
[36]Kim HI,Huang H,Cheepala S,et al.Curcumin inhibition of integrin(alpha6beta4)-dependent breast cancer cell motility and invasion[J].Cancer Prev Res,2008,1(5):385.
[37]Ye MN,Chen HF,Zhou RJ,et al.Effects of astragalus polysaccharide on proliferation and Akt phosphorylation of the basal-like breast cancer cell line[J].Journal of Chinese Integrative Medicine,2011,9(12):1339-1346.[叶媚娜,陈红风,周瑞娟,等.黄芪多糖对基底细胞样乳腺癌细胞增殖和Akt磷酸化的影响[J].中西医结合医学学报,2011,9(12):1339-1346.]
[38]Liao MJ,Ye MN,Zhou RJ,et al.Yiqi formula enhances the antitumor effects of erlotinib for treatment of triplenegative breast cancer xenografts.[J].Evid-Based Compl Alt,2013,2014(2):628712.
[39]Massihnia D,Galvano A,Fanale D,et al.Triple negative breast cancer:shedding light onto the role of PI3K/Akt/m TOR pathway[J].Oncotarget,2016,7(37):60712.