Resistance to Targeted Therapies in Renal Cancer: The Importance of Changing the Mechanism of Action
Por:
Duran, I, Lambea, J, Maroto, P, Gonzalez-Larriba, JL, Flores, L, Granados-Principal, S, Graupera, M, Saez, B, Vivancos, A, Casanovas, O
Publicada:
1 feb 2017
Resumen:
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.
Filiaciones:
Duran, I:
Hosp Univ Virgen del Rocio, Secc Oncol Med, Seville, Spain
Inst Biomed Sevilla, Lab Terapias Avanzadas & Biomarcadores Oncol, Seville, Spain
Lambea, J:
Hosp Clin Univ Lozano Blesa, Serv Oncol Med, Zaragoza, Spain
Maroto, P:
Hosp Santa Creu & Sant Pau, Serv Oncol Med, Barcelona, Spain
Gonzalez-Larriba, JL:
Hosp Clin San Carlos, Serv Oncol Med, Madrid, Spain
Flores, L:
Novartis Oncol, Barcelona, Spain
Granados-Principal, S:
Complejo Hosp Jaen, Serv Oncol Med, Jaen, Spain
Univ Granada, GENYO, Ctr Genom & Oncol Res, Pfizer,Andalusian Reg Govt,PTS Granada, Granada, Spain
Graupera, M:
Inst Invest Biomed Bellvitge IDIBELL, Barcelona, Spain
Saez, B:
Univ Zaragoza, Inst Univ Invest Nanociencia Aragon, Dept Bioquim Biol Mol & Celular, Zaragoza, Spain
Vivancos, A:
Univ Pompeu Fabra, Dept Bioquim & Biol Mol, Barcelona, Spain
Casanovas, O:
Inst Catala Oncol IDIBELL, ProCURE Res Program, Avinguda Gran Via 199-203, Barcelona 08907, Spain
Green Accepted
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