Abstract:
Despite substantial advances in targeting KRASG12C, tumor acquired resistance to KRASG12C inhibitors (KRASG12Ci) remains a major barrier to progress. Here, we report ATF3-driven asparagine metabolic reprogramming as a key convergence point of KRASG12Ci resistance. Multi-omics profiling of resistant models revealed a chronic activation of the integrated stress response (ISR) and a concomitant upregulation of asparagine synthesis. We found that the ISR-inducible transcription factor ATF3 was upregulated and directly transactivated asparagine synthetase (ASNS), driving asparagine production. Genetic ablation of ATF3 or ASNS restored KRASG12Ci sensitivity, whereas exogenous asparagine reconstituted resistance. This ATF3-ASNS axis was conserved in the patient-derived model of acquired KRASG12Ci resistance. Furthermore, pharmacological inhibition of the upstream ISR kinase PERK synergized with KRASG12Ci to overcome resistance. This study reveals a therapeutically targetable mechanism of asparagine metabolic reprogramming that facilitates KRASG12C inhibitor resistance.
