Mammalian Target of Rapamycin Inhibitors Resistance Mechanisms in Clear Cell Renal Cell Carcinoma

Abstract

Mammalian target of rapamycin (mTOR) is a kinase protein involved in PI3K/AKT signaling with a central role in the processes of cell growth, survival and angiogenesis. Frequent mutations of this pathway make upstream and downstream components novel targets for tailored therapy design. Two mTOR inhibitors – everolimus and temsirolimus - enable an increase in overall survival (OS) or progression-free survival (PFS) time in a treatment of renal cancer. Despite recent advances in renal cancer treatment, resistance to targeted therapy is common. Understanding of molecular mechanisms is the basis of drug resistance which can facilitate prediction of success or failure in combinational or sequential targeted therapy. The article provides current knowledge on the mTOR signaling network and gives insight into the mechanisms of resistance to mTOR inhibitors from the complex perspective of RCC biology. The mechanisms of resistance developed not only by cancer cells, but also by interactions with tumor microenvironment are analyzed to emphasize the role of angiogenesis in ccRCC pathogenesis. As recent studies have shown the role of PI3K/AKT-mTOR pathway in proliferation and differentiation of cancer stem cells, we discuss cancer stem cell hypothesis and its possible contribution to ccRCC resistance. In the context of drug resistance, we also elaborate on a new approach considering ccRCC as a metabolic disease. In conclusion we speculate on future developments in agents targeting the mTOR pathway taking into consideration the singular biology of ccRCC.

mTORC2 mediates CXCL12-induced angiogenesis

“…In addition, our in vivo data are supported by evidence from the treatment of renal cell carcinoma, which is a highly vascular neoplasm that is often treated with rapamycin analogs (rapalogs) [41]. The rapalogs improve overall survival or progression-free survival time, which is mediated primarily through the inhibition of mTORC1 [42], but these benefits are only observed in a minority of patients [43]. In fact, the responses are not long lasting and most of the patients experience progression of the disease while on the treatment [42].…”

“…One mechanism proposed to drive this resistance is the lack of mTORC2 inhibition [44]. Thus, the clinical importance of targeting mTORC2 with either prolonged or increased concentrations of rapamycin is now being highlighted [43]. Taken together, the data from both our in vitro and our in vivo studies identify a novel mechanism that links CXCL12/CXCR4 signaling with angiogenesis through mTORC2.…”

Metabolic tumor burden is associated with major oncogenomic alterations and serum tumor markers in patients with resected pancreatic cancer

“…It is well established that TP53, CDKN2A/p16, and SMAD4/DPC4 mutations occur during pancreatic carcinogenesis, but it is unknown whether these mutations are associated with the abnormal metabolic tumor burden detected by 18 F-FDG PET/CT. Nevertheless, abnormal expression profiles of TP53, CDKN2A/p16, and SMAD4/DPC4 are known to contribute to tumor malignancies and treatment-resistance [23][24][25][26][27]. Activation of transcription factor TP53 in response to a series of stimuli and stresses induces signaling pathways that affect anticancer mechanisms, including DNA repair, cell-cycle arrest and apoptosis.…”

Hormone signaling pathways as treatment targets in renal cell cancer (Review)

“…Mutations of VHL result in constitutive stabilization of the HIF-1α subunit, leading to highly angiogenic malignancy (9). This phenomenon occurs due to overexpression of vascular endothelial growth factor (VEGF), its receptors (VEGFR1, VEGFR2 and VEGFR3), and platelet-derived growth factor (PDGF) receptors in response to constitutive activation of HIF-1α (10,11).…”