Abstract
Abstract Cancer cells gain drug-tolerant states and evade therapy. In response to KRAS G12C inhibitor (G12Ci), KRAS mutant non-small cell lung cancer (NSCLC) cells maintain a drug-tolerant state by aurora kinase A (AURKA). AURKA can phosphorylate c-Raf to maintain new KRAS signaling, however, how AURKA becomes activated to cause KRAS G12Ci resistance is unclear. We show here that KRAS G12C + AURKA inhibition cause synthetic lethality in KRAS G12C NSCLC cells. LY3499446 (KRAS G12Ci) and LSN3321213 (aurora kinase A inhibitor) induced apoptosis that is independent of inhibited MAPK reactivation. Using high-content imaging that tracks single-cell fate during treatment, we observed that single-agent KRAS G12Ci induces G1 arrest in a sub-population of cells. Upon co-treatment with G12C + AURKAi, cells that are halted in G1 phase undergo early apoptosis, while those that initially evade G1 arrest and proceed through G2/M undergo apoptosis in subsequent G1. These data suggest the hypothesis that AURKA inhibition may increase the probability of G1 checkpoint-induced apoptosis by facilitating chromosomal misalignment and genomic instability. In summary, we provide clinical rationale for clinical testing of KRAS G12C + AURKA inhibitors. We also suggest a novel mechanism explaining the dependency of KRAS G12C resistant subpopulations on AURKA, leading to the opportunity to investigate the role of genomic instability in conferring KRAS G12Ci adaptive resistance. Citation Format: Chendi Li, Jeremy Chang, Mohammed U. Syed, Anahita Nimbalkar, Yi Shen, Steve Altschuler, Lani Wu, Xueqian Gong, Aaron Hata. Aurora kinase A inhibition overcome adaptive resistance to KRAS G12C inhibitor by G1-checkpoint induced apoptosis in KRAS non-small cell lung cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3868.
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