Resistance to Targeted Therapies in Renal Cancer: The Importance of Changing the Mechanism of Action

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• 作者：I. Duran ; J. Lambea ; P. Maroto ; J. L. González-Larriba ; Luis Flores…
• 刊名：Targeted Oncology
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：12
• 期：1
• 页码：19-35
• 全文大小：
• 刊物主题：Oncology; Biomedicine, general;
• 出版者：Springer International Publishing
• ISSN：1776-260X
• 卷排序：12

文摘

Renal cell carcinoma (RCC) is a complex disease characterized by mutations in several genes. Loss of function of the von Hippel-Lindau (VHL) tumour suppressor gene is a very common finding in RCC and leads to up-regulation of hypoxia-inducible factor (HIF)-responsive genes accountable for angiogenesis and cell growth, such as platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). Binding of these proteins to their cognate tyrosine kinase receptors on endothelial cells promotes angiogenesis. Promotion of angiogenesis is in part due to the activation of the phosphatidylinositol-3-kinase (PI3K)/AKT/mechanistic target of rapamycin (mTOR) pathway. Inhibition of this pathway decreases protein translation and inhibits both angiogenesis and tumour cell proliferation. Although tyrosine kinase inhibitors (TKIs) stand as the main first-line treatment option for advanced RCC, eventually all patients will become resistant to TKIs. Resistance can be overcome by using second-line treatments with different mechanisms of action, such as inhibitors of mTOR, c-MET, programmed death 1 (PD-1) receptor, or the combination of an mTOR inhibitor (mTORi) with a TKI. In this article, we briefly review current evidence regarding mechanisms of resistance in RCC and treatment strategies to overcome resistance with a special focus on the PI3K/AKT/mTOR pathway.References1.Siegel RL, Miller KD, Jemal A. Cancer statistics, 2015. CA Cancer J Clin. 2015;65(1):5–29. doi:10.3322/caac.21254.PubMedCrossRefGoogle Scholar2.Bajorin DF. Tumors of the kidney, bladder, ureters, and renal pelvis. In: Goldman L, Schafer AI, editors. Goldman’s Cecil Medicine. 24th ed. Philadelphia, PA: Elsevier Saunders; 2012. p. 1303–8.CrossRefGoogle Scholar3.Gerlinger M, Catto JW, Orntoft TF, Real FX, Zwarthoff EC, Swanton C. Intratumour heterogeneity in urologic cancers: from molecular evidence to clinical implications. 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Eur J Cancer. 2013;49(9):2134–42. doi:10.1016/j.ejca.2013.02.032.PubMedCrossRefGoogle ScholarCopyright information© Springer International Publishing Switzerland 2016Authors and AffiliationsI. Duran12J. Lambea3P. Maroto4J. L. González-Larriba5Luis Flores6S. Granados-Principal78M. Graupera9B. Sáez10A. Vivancos11O. Casanovas12Email author1.Sección de Oncología MédicaHospital Universitario Virgen del RocíoSevillaSpain2.Laboratorio de Terapias Avanzadas y Biomarcadores en OncologíaInstituto de Biomedicina de SevillaSevillaSpain3.Servicio de Oncología MédicaHospital Clínico Universitario Lozano BlesaZaragozaSpain4.Servicio de Oncología MédicaHospital de la Santa Creu i Sant PauBarcelonaSpain5.Servicio de Oncología MédicaHospital Clínico San CarlosMadridSpain6.Novartis OncologyBarcelonaSpain7.Servicio de Oncología MédicaComplejo Hospitalario de JaénJaénSpain8.GENYO, Centre for Genomics and Oncological Research (Pfizer/University of Granada/Andalusian Regional Government), PTS GranadaGranadaSpain9.Institut d’Investigació Biomèdica de Bellvitge-IDIBELLBarcelonaSpain10.Departmento de Bioquímica, Biología Molecular y Celular, Instituto Universitario de Investigación en Nanociencia de AragónUniversidad de ZaragozaZaragozaSpain11.Departamento de Bioquímica y Biología MolecularUniversidad Pompeu FabraBarcelonaSpain12.ProCURE Research Program, Institut Català d’Oncologia-IDIBELLL’Hospitalet de LlobregatBarcelonaSpain About this article CrossMark Publisher Name Springer International Publishing Print ISSN 1776-2596 Online ISSN 1776-260X About this journal Reprints and Permissions Co-published with