Abstract 1928: Targeting FAK to improve the therapy of KRAS G12C mutant cancers

Abstract Despite the pivotal role of KRAS G12C in tumor initiation and progression, currently available KRAS G12C inhibitors have relatively modest activity compared to other approved therapies targeting other classic oncogenic drivers. Fortunately, efforts to improve the anti-tumor response to KRAS G12C targeted therapy have benefited from the use of combination approaches. Here, we found that treatment with KRAS G12C inhibitors induces sustained activation of focal adhesion kinase (FAK) in KRAS G12C mutant cell lines from various cancer types, including non-small cell lung cancer, colorectal cancer, and pancreatic cancer. These results suggest a potential role for FAK in adaptive resistance to KRAS G12C inhibition and encourage us to explore the anticancer effects of combining the KRAS G12C inhibitor SY-5933 with a FAK inhibitor, CT-707. The cell viability and clonogenic assays using various KRAS G12C mutant cancer cell lines showed that the combination of SY-5933 and CT-707 synergistically inhibited cell growth. Mechanistically, this enhanced anti-proliferative effect is associated with a significant decrease in FAK activity and a more pronounced induction of cell cycle arrest and apoptosis. In vivo efficacy studies in multiple cell line derived xenograft (CDX) models, the combination of SY-5933 plus CT-707 consistently induced a more potent anti-tumor response than either monotherapy alone. In conclusion, our results demonstrate that CT-707 has the potential to enhance the efficacy of SY-5933 by suppressing adaptive FAK activation under KRAS G12C inhibition. This provides a rationale for an innovative combination therapy to improve outcomes in patients with KRAS G12C mutated cancers. Citation Format: Shuang Liu, Junfen Shi, Chang Lu, Miao Zhang, Ying Xin, Yan Zhu, Jijun Li, Hong Luo, Yinghui Sun. Targeting FAK to improve the therapy of KRAS G12C mutant cancers [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(6_Suppl):Abstract nr 1928.