PRMT1 blockade reverts resistance to KRAS (G12C) inhibition through modulating ferroptosis signalling

While Kirsten rat sarcoma virus (KRAS) G12C inhibitors (KRAS G12Ci) are successful in clinical practice, their long‑term efficacy is limited by acquired resistance, and effective combination strategies are urgently needed. In the present study, pancreatic and lung cancer cell lines resistant to KRAS G12Ci (AMG510/D‑1553) were established. Ribonucleic acid‑sequencing (RNA‑seq) identified significant alterations in ferroptosis‑related signaling in KRAS G12Ci‑resistant cells. Through in vivo and in vitro experiments, it was found that an increase occurred in the expression level of protein arginine methyltransferase 1 (PRMT1) in resistant cells. The combined inhibition of KRAS G12C and PRMT1 showed a stronger inhibitory effect on tumor growth than single‑target inhibition. Mechanistically, the inhibition of PRMT1 could make histone H4 at arginine 3 (H4R3me2a) less enriched in the promoter region of solute carrier family 7 member 11 (SLC7A11). This suggests that PRMT1 may promote the transcription of SLC7A11 via epigenetic regulation mediated by H4R3me2a. Thus, this inhibits ferroptosis and potentially contributes to the maintenance of the KRAS G12Ci‑resistant phenotype. In summary, elevated PRMT1 expression was associated with KRAS G12C inhibitor resistance, and pharmacological inhibition of PRMT1‑associated activity enhanced the efficacy of KRAS G12C inhibition partly through ferroptosis. Further genetic validation is required to establish the specific role of PRMT1. The results of the present study will provide new targets and a theoretical basis for overcoming KRAS‑targeted treatment resistance, and will also promote the clinical translation of combined therapy.