MTAP deletion is one of the most common genetic alterations in human cancer, occurring in more than 10% of lung and pancreatic adenocarcinomas. PRMT5 dependence in cells with MTAP deletions is a strong and prevalent synthetic lethal interaction. TNG908 has a novel MTA-cooperative binding mechanism that drives synthetic lethality with MTAP deletion, unlike PRMT5 inhibitors currently in clinical development, and is 15X selective for MTAPnull over MTAPWT cells. Approximately 30% of MTAPnull lung adenocarcinomas and 85% of MTAPnull pancreatic adenocarcinomas are also KRAS-mutant.
In vitro and in vivo preclinical studies were conducted using cell lines and xenograft models with defined MTAP and KRAS status.
In vitro studies in MTAPnull/KRAS-mutant cancer cell lines demonstrate that combination of MTAPnull-selective PRMT5 inhibitors with MAPK pathway inhibitors, including agents that inhibit ERK, MEK or KRAS, drive a synergistic combination benefit. Approximately 15% of MTAPnull lung adenocarcinomas are also KRASG12C-mutant. In an MTAPnull/KRASG12C-mutant lung adenocarcinoma xenograft model, combination of TNG908 and sotorasib at clinically relevant doses drove tumor regressions, which outperformed exposure-matched single agent activity for either compound, demonstrating a strong in vivo combination benefit.
These data suggest that treatment of KRASG12C-mutant lung adenocarcinoma with TNG908 and a KRASG12C inhibitor may be of clinical benefit in lung cancers with concurrent MTAP deletion and KRASG12C mutation.
Legal entity responsible for the study
K. Briggs, A. Tsai, M. Zhang, M.R. Tonini, C.B. Davis, K.M. Cottrell, J.P. Maxwell: Financial Interests, Personal, Full or part-time Employment: Tango Therapeutics; Financial Interests, Personal, Stocks/Shares: Tango Therapeutics. G. Corriea, E.W. Wilker: Financial Interests, Personal, Stocks/Shares: Tango Therapeutics. A. Huang: Financial Interests, Personal, Officer: Tango Therapeutics; Financial Interests, Personal, Full or part-time Employment: Tango Therapeutics; Financial Interests, Personal, Stocks/Shares: Tango Therapeutics.