# Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK–YAP Signaling

## TL;DR

Combining FAK and KRAS G12C inhibitors improves cancer treatment by reducing drug resistance and enhancing antitumor effects.

## Contribution

A novel combination therapy using FAK and KRAS G12C inhibitors to overcome resistance in KRAS G12C mutant cancers.

## Key findings

- KRAS G12C inhibition activates FAK, contributing to drug resistance.
- Combining FAK and KRAS G12C inhibitors synergistically reduces tumor growth and resistance.
- Aberrant FAK–YAP signaling is a key mechanism in resistance to KRAS G12C inhibitors.

## Abstract

KRAS mutation is one of the most prevalent genetic drivers of cancer development, yet KRAS mutations are until very recently considered undruggable. There are ongoing trials of drugs that target the KRAS G12C mutation, yet acquired drug resistance from the extended use has already become a major concern. Here, it is demonstrated that KRAS G12C inhibition induces sustained activation of focal adhesive kinase (FAK) and show that a combination therapy comprising KRAS G12C inhibition and a FAK inhibitor (IN10018) achieves synergistic anticancer effects. It can simultaneously reduce the extent of drug resistance. Diverse CDX and PDX models of KRAS G12C mutant cancer are examined and synergistic benefits from the combination therapy are consistently observed. Mechanistically, it is found that both aberrant FAK–YAP signaling and FAK‐related fibrogenesis impact on the development of KRAS G12C inhibitor resistance. This study thus illustrates the mechanism of resistance of cancer to the treatment of KRAS G12C inhibitor, as well as an innovative combination therapy to improve treatment outcomes for KRAS G12C mutant cancers.

Here, a therapeutic strategy is described for KRAS G12C mutant cancers by the combination of KRAS G12C and FAK inhibition. Mechanistically, the aberrant FAK‐YAP signaling hampers benefits from KRAS G12C inhibitors. The combination of KRAS G12C and FAK inhibitors produces synergistic antitumor effects, providing a regimen to obtain strengthened and prolonged treatment outcomes for KRAS G12C mutant cancers.