Targeting PI3K and mTORC2 in metastatic renal cell carcinoma: New strategies for overcoming resistance to VEGFR and mTORC1 inhibitors

Abstract

With the advent of molecularly targeted agents, treatment of metastatic renal cell carcinoma (mRCC) has improved significantly. Agents targeting the vascular endothelial growth factor receptor (VEGFR) and the mammalian target of rapamycin complex 1 (mTORC1) are more effective and less toxic than previous standards of care involving cytotoxic and cytokine therapies. Unfortunately, many patients relapse following treatment with VEGFR and mTORC1 inhibitors as a result of acquired resistance mechanisms, which are thought to lead to the reestablishment of tumor vasculature. Specifically, the loss of negative feedback loops caused by inhibition of mTORC1 leads to upregulation of downstream effectors of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway and subsequent activation of hypoxia-inducible factor, an activator of angiogenesis. De novo resistance involving activated PI3K signaling has also been observed. These observations have led to the development of novel agents targeting PI3K, mTORC1/2 and PI3K/mTORC1/2, which have demonstrated antitumor activity in preclinical models of RCC. Several agents-BKM120, BEZ235 and GDC-0980-are being investigated in clinical trials in patients with metastatic/ advanced RCC, and similar agents are being tested in patients with solid tumors. The future success of mRCC treatment will likely involve a combination of agents targeting the multiple pathways involved in angiogenesis, including VEGFR, PI3K and mTORC1/2.Renal cell carcinoma (RCC) accounts for more than 2% of all human cancers, and its incidence is steadily rising by approximately 2% per year.

Gene set enrichment analysis and ingenuity pathway analysis of metastatic clear cell renal cell carcinoma cell line

“…Another significant pathway that was reported with mRCC in our data set using both GSEA and IPA enrichment was PI3K/AKT/mTOR. This pathway has been studied with regard to mRCC in several studies (7,22,60).…”

Bromodomain-Containing Protein 4 (BRD4) Inhibition Sensitizes Palomid 529-Induced Anti-Renal Cell Carcinoma Cell Activity in Vitro and in Vivo

“…Recent studies have implied that concurrent blockage of mTORC1 and mTORC2 is more efficient than mTORC1 inhibitors in inhibiting RCC cells [27,29]. One possible reason could be that mTORC2 is as important as mTORC1 for RCC cell progression [28,44,45].…”

Network-based approaches for drug response prediction and targeted therapy development in cancer

“…Another way of resistance development is activation of non-related pathways that initiate favorable conditions for cancer propagation and metastasis. This phenomenon has been observed in treatment of renal cell carcinomas by the combination therapy via inhibition of VEGFR and mTORC1 that lead to compensatory mTORC2-mediated Akt and hypoxia-inducible factor-1 (HIF-1) activation and eventually angiogenesis ameliorating metastatic development [38].…”