Abstract 3842: Potent antitumor activity of the HSP90 inhibitor SNX-2112 in type 1 papillary renal cell carcinoma

Papillary renal-cell carcinoma (pRCC) is the second most common form of kidney cancer, accounting for 15 to 20% of all cases. There are currently no treatment options of proven benefit for patients with advanced pRCC. The type 1 subset of pRCC tumors are associated with gain of chromosome 7 and activating mutations of MET that could lead to aberrant MET pathway activation resulting in cell proliferation and anti-apoptotic signaling. While MET kinase inhibitors are active in some patients with type 1 pRCC, primary and acquired resistance is common, prompting us to investigate possible therapeutic alternatives. Heat shock protein 90 (Hsp90), which stabilizes numerous oncogenic proteins, including MET and several downstream mediators of MET activity, is an important regulator of cell proliferation and survival, and has attracted wide interest as a novel target for cancer therapy. Hsp90 inhibitors were also identified as molecules of interest based on antitumor activity against patient derived type 1 pRCC cell lines following quantitative high throughput screening (qHTS) with small molecule libraries. We hypothesized that inhibition of Hsp90 might provide a novel therapeutic approach for patients with pRCC tumors with MET pathway activation. SNX-2112 was chosen as a candidate Hsp90 inhibitor for further evaluation. Our data demonstrate that inhibition of the Hsp90 pathway is lethal to pRCC cell lines with MET pathway activation, and that treatment with SNX-2112 leads to the degradation of MET/pMET and its downstream signaling intermediates p-AKT, AKT, p-ERK. Furthermore, SNX-2112 leads to inhibition of critical downstream transcriptional targets of AKT and ERK, including VEGF, c-Myc and BIRC5. SNX-2112 has potent anti-tumor activity in vitro, inhibiting proliferation, clonogenicity and 3D-anchorage independent colony formation of MET activated pRCC cell lines. These data demonstrate that Hsp90 inhibition is a promising therapeutic strategy in Type 1 pRCC and is worthy of further preclinical and clinical evaluation. Citation Format: Roma Pahwa, Abhigya Giri, Carole Sourbier, Craig Thomas, W Marston Linehan, Len Neckers, Ramaprasad Srinivasan. Potent antitumor activity of the HSP90 inhibitor SNX-2112 in type 1 papillary renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3842.