Non-clear cell renal cell carcinoma: does the mammalian target of rapamycin represent a rational therapeutic target?

Abstract

Non-clear cell renal cell carcinomas (nccRCCs) comprise a heterogenous and poorly characterized group of tumor types for which few treatments have been approved. Although targeted therapies have become the cornerstones of systemic treatment for metastatic renal cell carcinoma, patients with nccRCC have been excluded from many pivotal clinical trials. As such, robust clinical evidence supporting the use of these agents in patients with nccRCC is lacking. Here, we review the disparate nccRCC subtypes, the criteria for diagnosis, and the prognoses associated with each subtype, in addition to evaluating the potential use of mammalian target of rapamycin (mTOR) inhibitors in treating patients with nccRCC. Both genetic analyses and preclinical research indicate a central role for mTOR in nccRCC; a therapy that targets this ubiquitous regulator of cellular signaling could prove efficacious across various tumor subtypes. Results from recent studies exploring targeted therapies as both monotherapy and combination therapy have provided early indications of efficacy in patients with nccRCC. Exploratory analyses support further research with the mTOR inhibitors everolimus and temsirolimus in patients with nccRCC. Current clinical practice guidelines support the use of mTOR inhibitors in patients with nccRCC; however, these recommendations are based on low levels of evidence. Further results from randomized, controlled clinical trials are needed to determine the optimal choice of therapy for patients with nccRCC. Results from ongoing clinical trials of mTOR inhibitors and other agents in nccRCC, as well as their impact on the nccRCC treatment paradigm, are eagerly awaited.

Figure 1.

Origin of renal carcinomas in the nephron [13].

Figure 2.

Renal tumor histology showing gross and microscopic features for each subtype: clear cell renal cell carcinoma (A, B), papillary renal cell carcinoma type 1 (C, D), papillary renal cell carcinoma type 2 (E, F), clear cell papillary renal cell carcinoma (G, H), oncocytoma (I, J), chromophobe renal cell carcinoma (K, L), tubulocystic renal cell carcinoma (M, N), mucinous tubular and spindle-cell renal cell carcinoma (O, P), MiTF/TFE translocation renal cell carcinoma of TFE3 (Q, R) and TFEB (S, T), collecting duct carcinoma (U, V), and sarcomatoid renal cell carcinoma (W, X).

Figure 3.

Signaling pathways in renal cell carcinoma. Binding of von Hippel-Lindau and hypoxia inducible factor (HIF) can be disrupted by genetic mutation or hypoxia, reducing proteolysis and accumulating HIF transcription factors. HIF accumulation can also result from mammalian target of rapamycin (mTOR) activation. Nuclear translocation of HIF leads to transcription of genes, including VEGF and PDGF, which ultimately results in angiogenesis. Temsirolimus and everolimus inhibit mTOR complex 1 kinase activity. Abbreviations: Akt, protein kinase B; HIF, hypoxia inducible factor; mTOR, mammalian target of rapamycin; mTORC1, mammalian target of rapamycin complex 1; mTORC2, mammalian target of rapamycin complex 2; PDGF, platelet-derived growth factor; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog; VEGF, vascular endothelial growth factor; VHL, von Hippel-Lindau. Reprinted with adaptation from Oosterwijk et al. [13] with permission.

Figure 4.

Genes known to cause kidney cancer and their relationship with the mammalian target of rapamycin signaling pathway. MET receptor activation results in physiological processes, including proliferation, invasion, and angiogenesis. Phosphorylation of protein kinase B downregulates tuberous sclerosis complex, increasing mammalian target of rapamycin complex 1 activity, which results in enhanced hypoxia-inducible factor (HIF)-mediated transcription. Mutations to fumarate hydrogenase and succinate dehydrogenase impair prolyl hydroxylase activity, causing dysregulation in HIF degradation. Abbreviations: Akt, protein kinase B; AMPK, AMP-activated protein kinase; FH, fumarate hydrogenase; FLCN, folliculin; FNIP, folliculin interacting protein; HGF, hepatocyte growth factor; HIF, hypoxia-inducible factors; LKB1, liver kinase B1; MET, hepatocyte growth factor receptor; mTORC1, mammalian target of rapamycin complex 1; mTORC2, mammalian target of rapamycin complex 2; PHD, prolyl hydroxylase; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog; Rheb, Ras-family GTPase; SDH, succinate dehydrogenase; TSC, tuberous sclerosis complex. Reproduced with adaptation from Linehan et al. [23] with permission.