Inhibition of HSP 90 is associated with potent anti-tumor activity in Papillary Renal Cell Carcinoma

Abstract

Background There is no universally accepted treatment for patients with advanced papillary renal cell carcinoma (PRCC). The presence of activating mutations in MET, as well as gain of chromosome 7, where the MET gene is located, are the most common genetic alterations associated with PRCC, leading to the clinical evaluation of MET tyrosine kinase inhibitors (TKIs) in this cancer. However, TKIs targeting MET selectively, as well as multitargeted TKIs with activity against MET demonstrate modest efficacy in PRCC and primary and secondary treatment failure is common; other approaches are urgently needed to improve outcomes in these patients. Methods High throughput screening with small molecule libraries identified HSP90 inhibitors as agents of interest based on antitumor activity against patient derived PRCC cell lines. We investigated the activity of the orally available HSP90 inhibitor, SNX2112 in vitro, using 2D/3D PRCC cell culture models and in vivo, in mice tumor xenograft models. The molecular pathways mediating antitumor activity of SNX2112 were assessed by Western blot analysis, Flow cytometry, RNA-seq analysis, Real Time qPCR and imaging approaches. Results SNX2112 significantly inhibited cellular proliferation, induced G2/M cell cycle arrest and apoptosis in PRCC lines overexpressing MET. In contrast to TKIs targeting MET, SNX2112 inhibited both MET and known downstream mediators of MET activity (AKT, pAKT1/2 and pERK1/2) in PRCC cell lines. RNAi silencing of AKT1/2 or ERK1/2 expression significantly inhibited growth in PRCC cells. Furthermore, SNX2112 inhibited a unique set of E2F and MYC targets and G2M-associated genes. Interestingly, interrogation of the TCGA papillary RCC cohort revealed that these genes were overexpressed in PRCC and portend a poor prognosis. Finally, SNX-2112 demonstrated strong antitumor activity in vivo and prolonged survival of mice bearing human PRCC xenograft. Conclusions These results demonstrate that HSP90 inhibition is associated with potent activity in PRCC, and implicate the PI3K/AKT and MEK/ERK1/2 pathways as important mediators of tumorigenesis. These data also provide the impetus for further clinical evaluation of HSP90, AKT, MEK or E2F pathway inhibitors in PRCC. Graphical Abstract

Proteomic analysis identifies HMGA2 as a novel biomarker of overall survival in papillary renal cell carcinoma

“…In a study on the comprehensive molecular characterization of PRCC, alteration of the MET gene (mutation, splice variant, or gene fusion) or gain of chromosome 7 copy number was identified in 81.3% of Type 1 tumor 38 . Two pathways about PI3K/AKT and MEK/ERK1/2 pathways are important mediators of PRCC tumorigenesis through their roles in promoting cell growth 39 . Using multiple public genetic datasets, enolase 2 was found to increase glycolysis and cell proliferation, leading to a worse prognosis 40 .…”

“… 38 Two pathways about PI3K/AKT and MEK/ERK1/2 pathways are important mediators of PRCC tumorigenesis through their roles in promoting cell growth. 39 Using multiple public genetic datasets, enolase 2 was found to increase glycolysis and cell proliferation, leading to a worse prognosis. 40 Multi‐omics profiling of PRCC disclosed an increasing glutathione level, which is the main substance to overcome reactive oxygen species.…”

Heat shock protein 90: biological functions, diseases, and therapeutic targets

“…71 Beyond the well-known HSP90 clients like the tumor suppressor p53 and the oncoprotein SRC, a myriad of other HSP90 clients, including protein kinases, telomerase, hypoxia-inducible factor 1α (HIF-1α), and Akt, are deeply entrenched in the processes that fuel tumor growth. 23,[111][112][113] It is worth noting that tumors exhibit a significant upregulation of HSP90 levels, and heightened HSP90 expression in breast cancer, for instance, has been linked to reduced patient survival rates. 114 Consequently, HSP90 stands as a pivotal enabler of oncogene addiction and a key player in facilitating the survival of cancer cells, and inhibition of HSP90 can lead to the degradation of these client proteins, making it a target for anticancer therapies.…”

“…HSP90, functioning as a molecular chaperone, assumes a critical role in promoting the survival of cancer cells, largely because of the substantial reliance of these cells on HSP90‐assisted signaling pathways 71 . Beyond the well‐known HSP90 clients like the tumor suppressor p53 and the oncoprotein SRC, a myriad of other HSP90 clients, including protein kinases, telomerase, hypoxia‐inducible factor 1α (HIF‐1α), and Akt, are deeply entrenched in the processes that fuel tumor growth 23,111–113 . It is worth noting that tumors exhibit a significant upregulation of HSP90 levels, and heightened HSP90 expression in breast cancer, for instance, has been linked to reduced patient survival rates 114 .…”

Dialog beyond the Grave: Necrosis in the Tumor Microenvironment and Its Contribution to Tumor Growth

“…A recent study demonstrated that plasma HSP90α level can be used as a prognostic biomarker for hepatocellular carcinoma [ 172 ]. HSP90 inhibition might be a novel strategy for advanced papillary renal cell carcinoma [ 173 ], metastatic triple-negative breast cancer [ 174 ], pancreatic carcinoma [ 175 ], prostate cancer [ 176 ], and glioma [ 177 ] treatment. HSP90 inhibition also improves the survival of patients with gastrointestinal stromal tumors [ 178 ] and overcomes resistance to molecular targeted therapy in glioma [ 179 ].…”