Abstract 5997: Network based mapping reveals mechanistic drivers and targetable hubs contributing to Sotorasib resistance in KRAS G12C lung cancer

Abstract KRAS mutations are among the most common oncogenic drivers in lung adenocarcinoma, present in 30% of NSCLC cases. Most occur at codon 12, impairing KRAS’s intrinsic GTPase activity and locking it in a constitutively active state. Although KRAS was long considered “undruggable,” the development of covalent inhibitors, such as sotorasib, which bind to the KRAS G12C GDP-bound form, marked a significant therapeutic advance. However, the clinical responses remain limited, as many patients exhibit intrinsic resistance or eventually develop acquired resistance. These limitations highlight that cancer cells expressing KRAS G12C were not solely dependent on KRAS signaling for survival. Instead, they adapt to therapeutic pressure by rewiring their underlying gene regulatory and protein-protein interaction networks. These networks are highly complex, coordinated, and dynamic in nature rather than fixed. Environmental cues, drug exposure, and intrinsic signaling programs can reshape network topology, generating new regulatory states that sustain tumor survival and drive resistance. Therefore, a systems-level examination of these topological transitions is essential for identifying the mechanistic basis of KRAS inhibitor resistance and identifying the upstream nodes that may serve as therapeutic vulnerabilities. Methods: Mass-spectrometry-based proteomic and phosphoproteomic profiling was performed on parental and isogenic resistant NCI-H23 cells, with and without sotorasib treatment. Network-based analyses were conducted to identify signaling alterations associated with the development of resistance. Results and Conclusion: The integrated analysis suggests that tolerance to KRAS G12C inhibition is not mediated by a single pathway, but rather by a coordinated network of mitotic, replication stress, RNA processing, and chromatin remodeling mechanisms. Upregulation of mitotic regulators (FOXM1, MELK, PLK4, NEK2), replication-stress proteins (RRM2, RFC3, MCM5/6, RPA2/3), and splicing/chromatin factors (CLK1, SRPK1, SRSF1 Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5997.