YAP/TAZ mediates resistance to KRAS inhibitors through inhibiting proapoptosis and activating the SLC7A5/mTOR axis.

ABSTRACT: KRAS mutations are frequent in various human cancers. The development of selective inhibitors targeting KRAS mutations has opened a new era for targeted therapy. However, intrinsic and acquired resistance to these inhibitors remains a major challenge. Here, we found that cancer cells resistant to KRAS G12C inhibitors also display cross-resistance to other targeted therapies, such as inhibitors of RTKs or SHP2. Transcriptomic analyses revealed that the Hippo-YAP/TAZ pathway is activated in intrinsically resistant and acquired-resistance cells. Constitutive activation of YAP/TAZ conferred resistance to KRAS G12C inhibitors, while knockdown of YAP/TAZ or TEADs sensitized resistant cells to these inhibitors. This scenario was also observed in KRAS G12D-mutant cancer cells. Mechanistically, YAP

SUBMITTER: Yang W 

PROVIDER: S-EPMC11665569 | biostudies-literature | 2024 Dec

REPOSITORIES: biostudies-literature