Targeting ATF3-mediated asparagine biosynthesis reverses acquired resistance to KRASᴳ¹²ᶜ inhibitors

Title : Targeting ATF3-mediated asparagine biosynthesis reverses acquired resistance to KRASᴳ¹²ᶜ inhibitors

Abstract:

Despite substantial advances in targeting KRAS^G12C, tumor acquired resistance to KRAS^G12C inhibitors (KRAS^G12Ci) remains a major barrier to progress. Here, we report ATF3-driven asparagine metabolic reprogramming as a key convergence point of KRAS^G12Ci 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^G12Ci sensitivity, whereas exogenous asparagine reconstituted resistance. This ATF3-ASNS axis was conserved in the patient-derived model of acquired KRAS^G12Ci resistance. Furthermore, pharmacological inhibition of the upstream ISR kinase PERK synergized with KRAS^G12Ci to overcome resistance. This study reveals a therapeutically targetable mechanism of asparagine metabolic reprogramming that facilitates KRAS^G12C inhibitor resistance.

Biography:

Yanjing Zhu is a Ph.D. candidate in Clinical Oncology at Fudan University Zhongshan Hospital, specializing in digestive system tumors. Her research focuses on tumor metabolism, immunotherapy, organoid models, and drug resistance mechanisms. She has published multiple first-author papers in high-impact journals such as Cell Reports Medicine and Hepatology, and leads two National Natural Science Foundation projects. Her work aims to advance precision oncology through translational research.