EGFR promotes ALKBH5 nuclear retention to attenuate N6-methyladenosine and protect against ferroptosis in glioblastoma.

Growth factor receptors rank among the most important oncogenic pathways, but pharmacologic inhibitors often demonstrate limited benefit as monotherapy. Here, we show that epidermal growth factor receptor (EGFR) signaling repressed N6-methyladenosine (m6A) levels in glioblastoma stem cells (GSCs), whereas genetic or pharmacologic EGFR targeting elevated m6A levels. Activated EGFR induced non-receptor tyrosine kinase SRC to phosphorylate the m6A demethylase, AlkB homolog 5 (ALKBH5), thereby inhibiting chromosomal maintenance 1 (CRM1)-mediated nuclear export of ALKBH5 to permit sustained mRNA m6A demethylation in the nucleus. ALKBH5 critically regulated ferroptosis through m6A modulation and YTH N6-methyladenosine RNA binding protein (YTHDF2)-mediated decay of the glutamate-cysteine ligase modifier subunit (GCLM). Pharmacologic targeting of ALKBH5 augmented the anti-tumor efficacy of EGFR and GCLM inhibitors, supporting an EGFR-ALKBH5-GCLM oncogenic axis. Collectively, EGFR reprograms the epitranscriptomic landscape through nuclear retention of the ALKBH5 demethylase to protect against ferroptosis, offering therapeutic paradigms for the treatment of lethal cancers. [Display omitted] • EGFR downregulates m6A levels by promoting ALKBH5 nuclear localization • SRC phosphorylates ALKBH5, reducing CRM1-mediated ALKBH5 nuclear export • EGFR-ALKBH5 protects GCLM decay via m6A to repress ferroptosis • Pharmacologic ALKBH5 inhibitors augment efficacy of EGFR and GCLM inhibitors Although growth receptor pathways commonly activate similar pathways, Lv et al. show that EGF signaling represses m6A levels in contrast to induction by PDGF. EGFR blocks ALKBH5 nuclear export, increasing m6A eraser function and suppression of ferroptosis through glutathione production. ALKBH5 inhibitors enhance the anti-tumor efficacy of EGFR or glutathione inhibitors. [ABSTRACT FROM AUTHOR]