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.
Targeted oncology. 2016 Nov 15 [Epub ahead of print]
I Duran, J Lambea, P Maroto, J L González-Larriba, Luis Flores, S Granados-Principal, M Graupera, B Sáez, A Vivancos, O Casanovas
Sección de Oncología Médica, Hospital Universitario Virgen del Rocío, Sevilla, Spain., Servicio de Oncología Médica, Hospital Clínico Universitario Lozano Blesa, Zaragoza, Spain., Servicio de Oncología Médica, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain., Servicio de Oncología Médica, Hospital Clínico San Carlos, Madrid, Spain., Novartis Oncology, Barcelona, Spain., Servicio de Oncología Médica, Complejo Hospitalario de Jaén, Jaén, Spain., Institut d'Investigació Biomèdica de Bellvitge-IDIBELL, Barcelona, Spain., Departmento de Bioquímica, Biología Molecular y Celular, Instituto Universitario de Investigación en Nanociencia de Aragón, Universidad de Zaragoza, Zaragoza, Spain., Departamento de Bioquímica y Biología Molecular, Universidad Pompeu Fabra, Barcelona, Spain., ProCURE Research Program, Institut Català d'Oncologia-IDIBELL, L'Hospitalet de Llobregat, Avinguda Gran Via, 199-203, 08907, Barcelona, Spain. .