Evidence for synergy between TNG908, an MTAPnull-selective PRMT5 inhibitor, and sotorasib in an MTAPnull/KRASG12C xenograft model

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Abstract 24P

Background

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 MTAP^null over MTAP^WT cells. Approximately 30% of MTAP^null lung adenocarcinomas and 85% of MTAP^null pancreatic adenocarcinomas are also KRAS-mutant.

Methods

In vitro and in vivo preclinical studies were conducted using cell lines and xenograft models with defined MTAP and KRAS status.

Results

In vitro studies in MTAP^null/KRAS-mutant cancer cell lines demonstrate that combination of MTAP^null-selective PRMT5 inhibitors with MAPK pathway inhibitors, including agents that inhibit ERK, MEK or KRAS, drive a synergistic combination benefit. Approximately 15% of MTAP^null lung adenocarcinomas are also KRAS^G12C-mutant. In an MTAP^null/KRAS^G12C-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.

Conclusions

These data suggest that treatment of KRAS^G12C-mutant lung adenocarcinoma with TNG908 and a KRAS^G12C inhibitor may be of clinical benefit in lung cancers with concurrent MTAP deletion and KRAS^G12C mutation.

Legal entity responsible for the study

Tango Therapeutics.

Funding

Tango Therapeutics.

Disclosure

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.