Morphoproteomics and biomedical analytics confirm the mTORC2/Akt pathway as a resistance signature and activated ERK and STAT3 as concomitant prosurvival/antiapoptotic pathways in metastatic renal cell carcinoma (RCC) progressing on rapalogs: Pathogenesis and therapeutic options

Abstract

BackgroundIt has been proposed that resistance to rapalog therapies in renal cell carcinoma (RCC) is due to adaptive switching from mammalian target of rapamycin complex 1 (mTORC1) to mTORC2.ObjectiveTo combine phosphoprotein staining and applied biomedical analytics to investigate resistance signatures in patients with metastatic RCC progressing on rapalog therapies.DesignWe applied morphoproteomic analysis to biopsy specimens from nine patients with metastatic RCC who continued to show clinical progression of their tumors while being treated with a rapalog.ResultsIn patients who were on temsirolimus or everolimus at the time of biopsy, a moderate to strong expression of phosphorylated (p)-mTOR (Ser 2448) in the nuclear compartment with concomitant expression of p-Akt (Ser 473) confirmed the mTORC2 pathway. Concomitant moderate to strong nuclear expression of p-ERK 1/2 (Thr202/Tyr204) and p-STAT3 (Tyr705) was confirmed. Histopathologic changes of hypoxic-type coagulative necrosis in 5 cases as well as identification of insulin-like growth factor-1 receptor (IGF-1R) expression and histone methyltransferase EZH2 in all tumors studied suggested that hypoxia also contributed to the resistance signature. Biomedical analytics provided insight into therapeutic options that could target such adaptive and pathogenetic mechanisms.ConclusionsMorphoproteomics and biomedical analytics confirm mTORC2/Akt as a resistance signature to rapalog therapy in metastatic RCC and demonstrate activation of the prosurvival ERK and STAT3 pathways and involvement of hypoxic pathways that contribute to pathogenesis of such adaptive resistance. These results highlight the need for a novel combinatorial therapeutic approach in metastatic RCC progressing on rapalogs.

Long Non-coding RNA CCAT1 Acts as an Oncogene and Promotes Sunitinib Resistance in Renal Cell Carcinoma

“…The MET/AXL-induced epithelial-mesenchymal transition conferred resistance to sunitinib ( 5 ). Concomitant hyperactivation of the extracellular signal-regulated kinase (ERK)/signal transducer and activator of transcription 3 (STAT3) and rapamycin complex 2 (mTORC2)/AKT contributed to anti-apoptosis of metastatic RCC ( 6 ). So far, the clinical trials that attempted to conquer the anti-angiogenesis were limited, urging an extensive understanding of resistance mechanisms.…”

Acquired resistance to temsirolimus is associated with integrin α7 driven chemotactic activity of renal cell carcinoma in vitro

“…Cell culture studies point to feedback activation of the PI3K-Akt signaling pathway, caused by inhibiting the mTOR complex 1 (mTORC1) [ 16 ]. Morphoproteomic analysis of biopsies from RCC patients who clinically progress despite temsirolimus or everolimus therapy has revealed constitutively activated STAT3 and ERK pathways in collaboration with the mTOR complex 2 (mTORC2) and Akt [ 17 ].…”

Prognostic significance of proteomics and multi-omics studies in renal carcinoma

“…The down-regulation of ARID1A protein expression was confirmed also in human RCC tissues. Some studies have addressed the role of apoptosis resistance as a driver of RCC progression [39,40]. The Xlinked inhibitor of apoptosis protein (XIAP) is a potent inhibitor of the caspase pathway, thereby promoting cell survival during tumour progression.…”