Resistance to targeted therapy in renal-cell carcinoma.
Therapeutic targeting of integral biological pathways, including those involving vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR), has produced robust clinical effects and revolutionised the treatment of metastatic renal-cell carcinoma (RCC). However, some patients are inherently resistant to these approaches and most, if not all, patients acquire resistance over time. As such, the biological basis for resistance to these targeted therapies and the clinical approach in this setting is of heightened interest. Emerging preclinical evidence suggests resistance is mediated via tumour and environmental changes, which allow for continued perfusion and tumour growth that is less reliant on VEGF. Furthermore, elements upstream of receptor blockade, such as hypoxia-inducible factor (HIF) and protein kinase B (AKT), in addition to pathways independent of VEGF or mTOR, could drive tumour growth despite adequate target blockade. These considerations provide a rational basis for combination or sequential therapy targeting these elements. Clinical data support activity of several agents in resistant patient populations, with large-scale clinical trials ongoing to more thoroughly test several postulations regarding the optimum clinical approach.
Department of Solid Tumor Oncology, Cleveland Clinic Taussig Cancer Institute, Glickman Urologic and Kidney Institute, 9500 Euclid Avenue/Desk R35, Cleveland, OH 44195, USA. rinib2@ccf.org
Brian I
BI
Rini
Michael B
MB
Atkins
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000473:pathology; D011494:Protein Kinases / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*
D000970:Antineoplastic Agents; D042461:Vascular Endothelial Growth Factor A; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases