TEAD Inhibitors Sensitize KRAS(G12C) Inhibitors via Dual Cell Cycle Arrest in KRAS(G12C)-Mutant NSCLC

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.