TEAD inhibitor K-975 enhances KRASG12C inhibitor adagrasib-mediated cancer cell proliferation inhibition via dual cell cycle arrest

Here we investigate the effect of the dual inhibition, in KRASG12C mutated NSCLC cells, using the KRASG12Ci adagrasib (MRTX849) and the pan-TEAD inhibitor (TEADi) K-975. We show that K-975 enhances adagrasib-induced tumor cell growth inhibition in cancer cells. Mechanistically, we detect a downregulation of MYC and E2F signatures and a downregulation of the G2/M checkpoint regulation, which result in the increase of G1 and the decrease of the G2/M cell cycle phases. These data suggest that the co-inhibition of KRASG12C and YAP1-TEAD leads to a specific switch in the mechanism of cancer cell killing.