TEAD Inhibitors Sensitize KRASG12C Inhibitors via Dual Cell Cycle Arrest in KRASG12C-Mutant NSCLC

Abstract

KRAS^G12C is one of the most common mutations detected in non-small cell lung cancer (NSCLC) patients, and it is a marker of poor prognosis. The first FDA-approved KRAS^G12C inhibitors, sotorasib and adagrasib, have been an enormous breakthrough for patients with KRAS^G12C mutant NSCLC; however, resistance to therapy is emerging. The transcriptional coactivators YAP1/TAZ and the family of transcription factors TEAD1-4 are the downstream effectors of the Hippo pathway and regulate essential cellular processes such as cell proliferation and cell survival. YAP1/TAZ-TEAD activity has further been implicated as a mechanism of resistance to targeted therapies. Here, we investigate the effect of combining TEAD inhibitors with KRAS^G12C inhibitors in KRAS^G12C mutant NSCLC tumor models. We show that TEAD inhibitors, while being inactive as single agents in KRAS^G12C-driven NSCLC cells, enhance KRAS^G12C inhibitor-mediated anti-tumor efficacy in vitro and in vivo. Mechanistically, the dual inhibition of KRAS^G12C and TEAD results in the downregulation of MYC and E2F signatures and in the alteration of the G2/M checkpoint, converging in an increase in G1 and a decrease in G2/M cell cycle phases. Our data suggest that the co-inhibition of KRAS^G12C and TEAD leads to a specific dual cell cycle arrest in KRAS^G12C NSCLC cells.