基于网络的图谱揭示了导致 KRAS G12C 肺癌 Sotorasib 耐药的机制驱动因素和可靶向枢纽

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&3, SUZ12, EED) creates a robust stress-adaptation network that enables survival under KRAS-G12C inhibition. This coordinated pathway maintains cell proliferation, stabilizes stalled forks, supports chromatin plasticity, and promotes the emergence of drug-tolerant persisters. Together, these data support a model in which sotorasib-exposed cells adapt by coupling mitotic and replication-stress programs with RNA and chromatin remodeling, thereby maintaining viability in a chromosomally unstable state that can give rise to drug-tolerant persisters and, ultimately, fully resistant clones. In addition, these findings also highlight a set of actionable vulnerabilities within the mitotic and replication-stress machinery that may be targeted to prevent or delay resistance to KRAS G12C inhibitors.