Abstract 1709: MAPK pathway alterations are a targetable vulnerability in bladder cancer

Abstract

Abstract Bladder cancer (BC) is the fourth most common cancer in males and accounts for about 80,000 new cases in the US. Approximately 25% patients with BC will present with muscle-invasive bladder cancer (MIBC) and for the past several decades the standard-of-care for MIBC and metastatic bladder cancer has been cisplatin-based chemotherapy. More recently, multiple immunotherapeutic agents have been approved but only a subset of patients respond to these treatments and therefore novel therapeutic strategies are needed to expand treatment options and improve clinical outcomes for BC patients. Large-scale genomic studies of MIBC have identified numerous recurrent genomic alterations including mutations, copy number alterations, and chromosomal translocations. Using publicly available patient datasets, we identified ~20% of MIBC patients harboring alterations in genes involved in the mitogen-activated protein kinase (MAPK) pathway and their upstream activators. RAF1 copy number amplification was the most predominant alteration followed by activating HRAS mutations. Leveraging our institutional cohorts of bladder cancer specimens, we defined the frequency of these alterations and validated RAF1 amplification in a subset of cases using fluorescence in situ hybridization. To functionally define the role of MAPK pathway alterations in BC, we tested activity of RAF and MEK inhibitors in BC cell line models with diverse MAPK pathway alterations including RAF1 amplification and HRAS/NRAS mutations. We found that these MAPK pathway altered models displayed increased sensitivity to RAF/MEK inhibition compared to MAPK-unaltered models. We further demonstrated the feasibility of preclinically targeting these alterations in mouse models of BC using cell line and patient-derived-xenografts. Additionally, we tested the impact of MAPK pathway modulation on tumor extrinsic properties including changes in the tumor microenvironment that could potentially affect responses to immunotherapeutic agents. Taken together, we have identified MAPK pathway alterations as a novel dependency in BC that can be targeted with emerging RAF inhibitors. Citation Format: Raie Bekele, Amruta Samant, Timothy Hanlon, Kent Mouw. MAPK pathway alterations are a targetable vulnerability in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1709.