靶向ATF3介导的天冬酰胺生物合成逆转KRAS G12C抑制剂获得性耐药

Abstract

Despite substantial advances in targeting KRAS G12C , tumor acquired resistance to KRAS G12C inhibitors (KRAS G12C i) remains a major barrier to progress. Here, we report ATF3-driven asparagine metabolic reprogramming as a key convergence point of KRAS G12C i 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 KRAS G12C i sensitivity, whereas exogenous asparagine reconstituted resistance. This ATF3-ASNS axis was conserved in the patient-derived model of acquired KRAS G12C i resistance. Furthermore, pharmacological inhibition of the upstream ISR kinase PERK synergized with KRAS G12C i to overcome resistance. This study reveals a therapeutically targetable mechanism of asparagine metabolic reprogramming that facilitates KRAS G12C inhibitor resistance. The alternative text for this image may have been generated using AI.