Abstract 1935: The FAK/SRC axis mediates resistance to KRAS G12C inhibitors and its blockade can overcome KRAS inhibitor resistance

Abstract Activating mutations in KRAS are found in approximately 30% of non-small cell lung cancer (NSCLC), and among all KRAS mutations, KRAS G12C is the most frequent variant in NSCLC, with a prevalence of approximately 14%. KRAS G12C inhibitors, sotorasib and adagrasib are FDA approved for locally advanced or metastatic KRAS G12C-positive NSCLC. However, clinical evidence suggests that there are various factors limiting the efficacy of KRAS G12C inhibitors in patients with KRAS G12C-positive NSCLC, highlighting the urgent need for novel treatment strategies or combinations to improve efficacy. Therefore, we sought to identify effective combinations to enhance the efficacy of KRAS G12C inhibitors using in vitro and in vivo models of KRAS G12C-positive NSCLC. Employing a high throughput in vitro drug screening effort using KRAS mutant NSCLC cell lines, we observed that Focal Adhesion Kinase (FAK) and Steroid Receptor Coactivator (SRC) inhibitors produced a synergistic effect when combined with KRAS G12C inhibitors adagrasib or sotorasib. As determined by reverse phase array and Western blotting, in H358, H23, HCC44, and H2122 cells, KRAS inhibitor treatment alone resulted in an initial suppression of RAS/MAPK and AKT pathway activation which was followed by upregulation of multiple receptor tyrosine kinases and integrins which contributed to the re-activation of the RAS/MAPK and AKT pathways after 24-48 hours. We identified FAK as a key downstream mediator of these bypass pathways. FAK/SRC inhibitors enhanced the efficacy of KRAS G12C inhibitors by preventing this feedback activation. Moreover, we observed increased FAK activation in H358 NSCLC cell lines with acquired resistance to adagrasib or sotorasib as compared to parental cells, and FAK/SRC inhibitors re-sensitized resistant cells to KRAS G12C inhibitors. Using a xenograft model of human KRAS mutant NSCLC, we determined that the combination of repotrectinib, a FAK/SRC inhibitor, and a KRAS G12C inhibitor significantly suppressed tumor growth as compared to KRAS G12C inhibitors alone, and this combination was well tolerated. Overall, our findings indicate that activation of FAK is a key mechanism of adaptive feedback and acquired resistance to KRAS G12C inhibitors in KRAS G12C-positive NSCLC and highlight the therapeutic potential of FAK/SRC inhibitors in combination with KRAS G12C inhibitors. These data support the clinical testing of the combination of FAK/SRC inhibitors and KRAS G12C inhibitors in patients with KRAS G12C-positive NSCLC. Citation Format: Yuji Shibata, Hibiki Udagawa, Monique B. Nilsson, Jacqulyne Robichaux, Ana Galan-Cobo, Marcelo Negrao, David P. Molkentine, Junqin He, Alissa Poteete, Yu Qian, Qian Huang, Ferdinandos Skoulidis, John V. Heymach. The FAK/SRC axis mediates resistance to KRAS G12C inhibitors and its blockade can overcome KRAS inhibitor resistance abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 1935.