KRAS Mutation Confers Lung Adenocarcinoma Platinum Resistance by Hijacking ALKBH5 Post-translational Modifications–mediated DNA Damage Response

ABSTRACT: Constitutively active mutations of KRAS frequently occur in non-small cell lung adenocarcinoma cells (NSCLC). However, the relationship between KRAS constitutive mutations and platinum drug resistance in NSCLC, as well as the underlying mechanism, remains unclear. In this study, we have identified that KRAS constitutive mutations confer resistance to platinum-based drugs in NSCLC. Mechanistically, KRAS mediates platinum resistance in NSCLC cells by enhancing ERK/JNK signaling, which controls post-translational modifications (PTMs) of ALKBH5. This, in turn, leads to an upregulation of m6A methylation in mRNA transcripts related to DNA repair genes. Consequently, the increased m6A methylation of these transcripts results in their mRNA stabilization, thereby protecting NSCLC cells from platinum-induced DNA damage and apoptosis, ultimately conferring platinum drug resistance in NSCLC. Furthermore, our observations indicate that blocking the KRAS mutation-induced increase in m6A methylation of DNA repair-related genes can sensitize NSCLC cells harboring KRAS mutations to platinum exposure. This can be achieved either by overexpressing a SUMOylation-deficient mutant of ALKBH5 or by pharmacologically inhibiting METTL3 enzymatic activity using a small molecule. These interventions significantly enhance the sensitivity of KRAS mutant-bearing NSCLC cells to platinum-based treatments both in vitro and in vivo. In summary, our study uncovers a previously unrecognized mechanism involving KRAS mutations, ALKBH5 PTMs, and increased mRNA m6A levels in DNA repair-related genes, which collectively promote platinum resistance in NSCLC cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE268671 | GEO | 2025/02/19

REPOSITORIES: GEO