The role of mTOR inhibition as second-line therapy in metastatic renal carcinoma: clinical evidence and current challenges

Abstract

Sequential treatment with targeted agents is the standard of care for patients with metastatic renal cell carcinoma (mRCC). Although first-line therapy with tyrosine kinase inhibitors (TKIs) is recommended for most patients, eventually all patients become resistant to them. Therefore, optimal selection of second-line therapy is crucial. Areas covered: We have reviewed the recent literature through pubmed search and recent congress presentations to briefly describe the clinical evidence for mTOR inhibition as a valid strategy in the treatment of mRCC after progression during anti-VEGFR therapy. In addition, we outline the management of adverse events associated with these agents, highlighting the importance of switching to an alternative mechanism of action to overcome resistance to TKI and to decrease cumulative toxicity associated with sequential treatments of the same type. Expert commentary: The choice of subsequent therapy after progression to first-line is not clear. Although the new drugs cabozantinib and nivolumab have shown to be superior that everolimus, still it is unknown which patients may benefit from these therapies in second-line, so treatment should be personalized to each patient and should consider approaches with different mechanisms of action.

mTOR Signaling in Cancer and mTOR Inhibitors in Solid Tumor Targeting Therapy

“…For metastatic renal cell carcinoma (mRCC), temsirolimus and everolimus are the only mTOR inhibitors authoried by the US FDA. The clinical data demonstrated that mTOR inhibitors can treat mRCC effectively as long as the adverse events were appropriately handled [183]. As reported, ccRCC patients harboring TSC1 mutation tended to respond to mTOR inhibitors [184].…”

Autophagy Function and Dysfunction: Potential Drugs as Anti-Cancer Therapy

“…Temsirolimus and everolimus are able to inhibit mTORC1 activation, leading to survival benefits in advanced ccRCC patients (Global ARCC trial) [126,127]. In another study, patients carrying mTOR , TSC1, or TSC2 mutations [128] treated with mTOR inhibitors (everolimus and temsirolimus) were found to benefit more patients with rapid disease progression [129].…”

Molecular and Metabolic Subtypes in Sporadic and Inherited Clear Cell Renal Cell Carcinoma

“…Direct inhibitors of transcription factor HIF2α have been developed, which expands therapeutic targeting to several HIF activities in addition to angiogenesis [20,21]. Two other therapies include inhibitors of the mTOR pathway [22,23], and most recently, therapies to reestablish immune responses to cancer cells [24,25]. In contrast to other solid cancers, there are no therapies targeting cancer cells by drugs with direct cytotoxic activity in ccRCC.…”