肾癌靶向治疗耐药的生物学机制研究进展
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摘要
肾细胞癌是我国泌尿系统最常见的恶性肿瘤。肾细胞癌对放、化疗具有高度抵抗性,免疫治疗有效率极低且有明显副作用。分子靶向药物为晚期肾癌治疗揭开了崭新的一页,但靶向治疗耐药显著影响了其临床疗效。本文将就肾癌对靶向药物耐受的分子机制最新进展作一综述,以期为寻找全新的作用靶点提供新的思路。
Renal cell carcinoma is the most common malignant tumor of urinary system in China.Renal cell carcinoma is highly resistant to radiotherapy and chemotherapy,and the immunotherapy is very less effective and remains significant side effects.Molecular targeted drugs have opened a new page for the treatment of advanced renal cell carcinoma,but targeted drug resistance has significantly affected its clinical efficacy.This article will review the latest progress of molecular mechanisms of drug resistance in renal cell carcinoma,in order to provide a new idea for discovering new targets.
Renal cell carcinoma is the most common malignant tumor of urinary system in China.Renal cell carcinoma is highly resistant to radiotherapy and chemotherapy,and the immunotherapy is very less effective and remains significant side effects.Molecular targeted drugs have opened a new page for the treatment of advanced renal cell carcinoma,but targeted drug resistance has significantly affected its clinical efficacy.This article will review the latest progress of molecular mechanisms of drug resistance in renal cell carcinoma,in order to provide a new idea for discovering new targets.
引文
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[2] Rassy EE,Khoury AR,Ibrahim N,et al.The current state of immune checkpoint inhibitors in the first-line treatment of renal cancer[J].Immunotherapy,2018,10(12):1047-1052.
[3] Lopez JI,Pulido R,Cortes JM,et al.Potential impact of PD-L1 (SP-142) immunohistochemical heterogeneity in clear cell renal cell carcinoma immunotherapy[J].Pathol Res Pract,2018,214(8):1110-1114.
[4] di Martino S,De Luca G,Grassi L,et al.Renal cancer:New models and approach for personalizing therapy[J].J Exp Clin Cancer Res,2018,37(1):217.
[5] Mallikarjuna P,Sitaram RT,Landstrom M,et al.VHL status regulates transforming growth factor-beta signaling pathways in renal cell carcinoma[J].Oncotarget,2018,9(23):16297-16310.
[6] Duran I,Lambea J,Maroto P,et al.Resistance to targeted therapies in renal cancer:The importance of changing the mechanism of action[J].Target Oncol,2017,12(1):19-35.
[7] Hagiwara N,Watanabe M,Iizuka-Ohashi M,et al.Mevalonate pathway blockage enhances the efficacy of mTOR inhibitors with the activation of retinoblastoma protein in renal cell carcinoma[J].Cancer Lett,2018,431:182-189.
[8] Figlin RA,Kaufmann I,Brechbiel J.Targeting PI3K and mTORC2 in metastatic renal cell carcinoma:New strategies for overcoming resistance to VEGFR and mTORC1 inhibitors[J].Int J Cancer,2013,133(4):788-796.
[9] Cao P,Jiang XJ,Xi ZJ.Sunitinib induces autophagy via suppressing Akt/mTOR pathway in renal cell carcinoma[J].Journal of Peking University(Health Sciences),2016,48(1):584-589.
[10] Chauhan A,Semwal DK,Mishra SP,et al.Combination of mTOR and MAPK inhibitors-a potential way to treat renal cell carcinoma[J].Med Sci (Basel),2016,4(4):E16.
[11] Earwaker P,Anderson C,Willenbrock F,et al.RAPTOR up-regulation contributes to resistance of renal cancer cells to PI3K-mTOR inhibition[J].PLoS One,2018,13(2):e0191890.
[12] Zhou J,Zhu G,Huang J,et al.Non-canonical GLI1/2 activation by PI3K/AKT signaling in renal cell carcinoma:A novel potential therapeutic target[J].Cancer Lett,2016,370(2):313-323.
[13] Bhatt RS,Wang X,Zhang L,et al.Renal cancer resistance to antiangiogenic therapy is delayed by restoration of angiostatic signaling[J].Mol Cancer Ther,2010,9(10):2793-2802.
[14] Makhov P,Joshi S,Ghatalia P,et al.Resistance to systemic therapies in clear cell renal cell carcinoma:Mechanisms and management strategies[J].Mol Cancer Ther,2018,17(7):1355-1364.
[15] Huang D,Ding Y,Zhou M,et al.Interleukin-8 mediates resistance to antiangiogenic agent sunitinib in renal cell carcinoma[J].Cancer Res,2010,70(3):1063-1071.
[16] Shojaei F,Lee JH,Simmons BH,et al.HGF/c-Met acts as an alternative angiogenic pathway in sunitinib-resistant tumors[J].Cancer Res,2010,70(24):10090-10100.
[17] Cancer Genome Atlas Research Network.Comprehensive molecular characterization of clear cell renal cell carcinoma[J].Nature,2013,499(7456):43-49.
[18] Shintani S,Kusano K,Ii M,et al.Synergistic effect of combined intramyocardial CD34+ cells and VEGF2 gene therapy after MI[J].Nat Clin Pract Cardiovasc Med,2006,Suppl 1:S123-128.
[19] Dietz S,Sultmann H,Du Y,et al.Patient-specific molecular alterations are associated with metastatic clear cell renal cell cancer progressing under tyrosine kinase inhibitor therapy[J].Oncotarget,2017,8(43):74049-74057.
[20] Cai W,Huang J,Yuan Y,et al.Sunitinib or sorafenib as neoadjuvant therapy may not improve the survival outcomes of renal cell carcinoma with tumor thrombus[J].Urol Int,2018,101(4):391-399.
[21] Hata A,Katakami N,Kaji R,et al.Afatinib plus bevacizumab combination after acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer:Multicenter,single-arm,phase 2 trial (ABC study)[J].Cancer,2018,124(19):3830-3838.
[22] Kono SA,Heasley LE,Doebele RC,et al.Adding to the mix:Fibroblast growth factor and platelet-derived growth factor receptor pathways as targets in non-small cell lung cancer[J].Curr Cancer Drug Targets,2012,12(2):107-123.
[23] Miao D,Margolis CA,Gao W,et al.Genomic correlates of response to immune checkpoint therapies in clear cell renal cell carcinoma[J].Science,2018,359(6377):801-806.
[24] Takeuchi H,Tokuyama N,Kuroda I,et al.Molecular targeted therapies of renal cell carcinoma considering life stage of the patient:Two case reports[J].Exp Ther Med,2018,15(4):3976-3980.
[25] Ishihara H,Takagi T,Kondo T,et al.Efficacy and safety of third-line molecular-targeted therapy in metastatic renal cell carcinoma resistant to first-line vascular endothelial growth factor receptor tyrosine kinase inhibitor and second-line therapy[J].Int J Clin Oncol,2018,23(3):559-567.
[26] Kitano H,Kitadai Y,Teishima J,et al.Combination therapy using molecular-targeted drugs modulates tumor microenvironment and impairs tumor growth in renal cell carcinoma[J].Cancer Med,2017,6(10):2308-2320.
[27] Zhu J,Armstrong AJ,Friedlander TW,et al.Biomarkers of immunotherapy in urotha:PD-L1,tumor mutatioelial and renal cell carcinomnal burden,and beyond[J].J Immunother Cancer,2018,6(1):4.