MXD4 enhances resistance to KRAS G12C‑targeted therapy in lung adenocarcinoma by suppressing ACSL4‑mediated ferroptosis

Rákkutatás · NSCLC

MXD4 specifically suppresses ferroptosis, rather than apoptotic or necrotic pathways, by repressing ACSL4 expression and blocking its catalytic synthesis of phosphatidylethanolamine‑polyunsaturated fatty acids (PE‑PUFAs).

KRAS G12C‑targeted therapies have transformed the treatment of KRAS G12C‑mutant lung adenocarcinoma. However, acquired resistance to these therapies, whose underlying molecular mechanisms are not fully understood, presents a major obstacle to achieving long‑term therapeutic success. By generating fulzerasib‑ and garsorasib‑resistant H23 and H2122 cell lines and performing transcriptomic profiling, the study identified up‑regulation of MXD4 in resistant cells. CRISPR/Cas9 knockout or siRNA knockdown of MXD4 restored sensitivity to multiple KRAS G12C inhibitors (fulzerasib, garsorasib, sotorasib, adagrasib). MXD4 specifically suppresses ferroptosis by repressing ACyl‑CoA synthetase long‑chain family member 4 (ACSL4) expression, blocking its catalytic synthesis of phosphatidylethanolamine‑polyunsaturated fatty acids (PE‑PUFAs). ChIP‑seq and dual‑luciferase assays confirmed MXD4 binds the ACSL4 promoter. MXD4 knockout sensitised patient‑derived organoids and nude mice to KRAS G12C inhibitors, demonstrating the MXD4‑ACSL4 axis as a novel resistance mechanism and a potential therapeutic target.

This finding reveals a new transcriptional mechanism driving acquired resistance to KRAS G12C inhibitors in lung adenocarcinoma, identifies MXD4 as a driver of resistance, and proposes targeting the MXD4‑ACSL4 axis to overcome therapeutic failure.

Bizonyítékszint: Korai humán adat. Kis vagy feltáró emberi adat.

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