Targeting Protein Interaction Network Plasticity Sensitizes Lung Cancer Cells Refractory to the KRAS Inhibitor Sotorasib

Drug resistance remains a major obstacle in KRASG12C targeted cancer therapy. Further, lung cancer cells refractory to sotorasib are sensitive to adagrasib, although both drugs covalently target the same cysteine residue. Here, employing proteomic and phospho-proteomic profiling, we show that the two drugs induce distinct intracellular signaling and conformational changes in KRAS, resulting in differential rewiring of the KRAS protein interaction network (PIN). Rewiring facilitates KRAS-independent survival pathways, notably involving cyclin-dependent kinases (CDK). CDK1 is a key hub protein, and its inhibition with dinaciclib resensitized refractory cells to sotorasib in vitro, in patient-derived organoids, and in vivo. Furthermore, combining dinaciclib with sotorasib produced synergistic effects across multiple KRASG12C-driven cancers, including lung, pancreatic, and gastrointestinal tumors. In addition, dinaciclib also synergized with other KRAS inhibitors such as adagrasib, divarasib, and RMC-6236. Cell cycle analysis revealed that this synergy resulted from the blockade of S-phase entry. These findings highlight non-genetic mechanisms and PIN plasticity as drivers of adaptive resistance and identify combination therapy targeting CDK1 as a promising therapeutic strategy.