Adaptive Feedback Signaling Through the FAK/SRC Pathway Promotes KRAS G12C Inhibitor Resistance

Allele-specific KRAS inhibitors, such as the KRAS^G12C inhibitors sotorasib and adagrasib, have demonstrated clinical activity as monotherapy, but adaptive signaling in response to KRAS pathway inhibition can promote resistance and limit the efficacy of these drugs. More effective combinatorial strategies are sorely needed to enhance efficacy and improve clinical outcomes in this patient population.

Using a high-throughput drug-screening approach and preclinical models, we investigated effective combinatorial strategies that enhance the efficacy of KRAS G12C inhibitors and prevent the emergence of resistance.

We identified that the focal adhesion kinase (FAK)/SRC pathway is a key mediator of the feedback activation of RAS/MAPK and AKT pathways triggered by the activation of multiple receptor tyrosine kinases and integrins in response to KRAS inhibitor treatment. Consistent with this observation, FAK and SRC inhibitors were found to synergize with KRAS inhibitors in preclinical models, and FAK/SRC inhibitors resensitized cells with acquired KRAS inhibitor resistance to sotorasib. Using xenograft models, we observed that pharmacologic blockade of FAK enhanced the antitumor activity of KRAS inhibitors.

These data highlight the therapeutic potential of FAK/SRC inhibitors to mitigate adaptive signaling induced by KRAS inhibition and enhance the clinical activity of KRAS inhibitors.