Abstract 4221: Anti-Tumor activity of the multityrosine kinase inhibitor dasatinib in type 1 papillary renal cell carcinoma

Abstract

Abstract Papillary renal cell carcinoma (PRCC) is a heterogeneous group of tumors accounting for 15-20% of all kidney tumors. PRCC is comprised of several histologically and genetically distinct subtypes, each characterized by a unique clinical course and response to therapy. There is no clearly accepted standard for treatment of most patients with advanced PRCC. Type 1 PRCC, the most common variant, is associated with activating mutation of MET gene (15% patients) and gain of chromosome 7 and 17 (~70-80% patients). Gain of function mutations in MET constitutively activate MET signaling leading to cell proliferation, and inhibition of apoptotic signals. It has been proposed that gain of chromosome 7 might provide an alternative means of activating MET signaling since both MET and its ligand HGF are located on chromosome 7. However, the clinical activity of MET tyrosine kinase inhibitors (TKIs) is modest and restricted largely to patients with MET TK domain mutations. Similarly, preclinical evaluation of MET TKIs in patient derived type 1 PRCC cell lines with A) MET TK domain mutations, or B) WT MET with copy number alterations, reveals modest anti-tumor activity. In order to identify effective alternative pharmacologic approaches, a high throughput screen of ~1912 small molecules directed against oncologically relevant targets was performed against four type 1 PRCC cell lines. Based on the screen, Src kinase inhibitors, including dasatinib, were identified as agents of interest for further investigation. Treatment with dasatinib was associated with potent antitumor activity against both MET mutant and WT MET type 1 PRCC cell lines in vitro. Dasatinib inhibited cell viability, clonogenicity and 3D-anchorage independent colony formation which may be partially attributed to G0-G1 cell cycle arrest. Treatment of mice bearing type 1 PRCC xenografts with dasatinib demonstrated potent tumor growth inhibition. Proteome phospho-kinase array and western blotting performed to further understand the critical pathways mediating dasatinib induced growth inhibition demonstrated downregulation of an array of molecules in addition to pSrc, including EGFR/pEGFR, pAkt, pTOR and p70S6kinase. RNA sequencing analysis revealed that dasatinib treatment inhibited Myc and E2F target genes BUB1, BIRC5, PLK1, TPX2 and CEP55. Interestingly, interrogation of the TCGA papillary RCC cohort reveals that all five genes are overexpressed in PRCC and portend a poor prognosis. These data suggest that dasatinib has anti-tumor activity in type 1 PRCC and may be worthy of further exploration in the clinic. The activity of dasatinib may be mediated in part by inhibition of Src, but other pathways may also be important and require further study. Citation Format: Roma Pahwa, Janhavi Dubhashi, Abhigya Giri, Craig Thomas, Michele Ceribelli, Parthav Jailwala, Alexei Lobanov, Anand Singh, Carole Sourbier, Christopher J. Ricketts, Cathy D. Vocke, Youfeng Yang, W. Marston Linehan, Ramaprasad Srinivasan. Anti-Tumor activity of the multityrosine kinase inhibitor dasatinib in type 1 papillary renal cell carcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4221.