EGFR helps keep ALKBH5 in the nucleus to reduce RNA modification and protect brain tumor cells from ferroptosis

Epidermal growth factor receptor (EGFR) signaling is associated with repression of N-methyladenosine (mA) levels in glioblastoma stem cells (GSCs).

• Targeting EGFR, either genetically or pharmacologically, increases mA levels in GSCs.
• Activated EGFR promotes phosphorylation of the mA demethylase ALKBH5 by the non-receptor tyrosine kinase SRC.
• This phosphorylation inhibits the export of ALKBH5 from the nucleus, allowing sustained mRNA mA demethylation.
• ALKBH5 plays a critical role in regulating ferroptosis through mA modulation and decay of the GCLM protein.
• Inhibiting ALKBH5 enhances the anti-tumor effects of therapies targeting EGFR and GCLM.
• EGFR may alter the epitranscriptomic landscape to prevent ferroptosis, which could inform new cancer treatments.

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