Adaptive Regulation of dNTP Homeostasis Confers Osimertinib Resistance in EGFR-Mutant Non-small Cell Lung Carcinoma - PubMed
6 hours ago
- #osimertinib resistance
- #dNTP homeostasis
- #EGFR-mutant NSCLC
- Osimertinib suppresses RRM2 expression by downregulating MYBL2, disrupting dNTP homeostasis in EGFR-mutant NSCLC.
- Cells activate a compensatory pathway involving RRM2B via TNNT3, regulated by CHK2 signaling, to counteract osimertinib-induced replication stress.
- Inhibition of CHK2 or combined CHK1/2 blockade impairs RRM2B induction, exacerbates replication stress, and delays osimertinib resistance in models.
- EGFR-mutant NSCLC relies on EGFR-MYBL2-RRM2 and CHK2-TNNT3-RRM2B pathways to maintain dNTP pools under osimertinib pressure.
- Disrupting this signaling network sensitizes tumors to osimertinib and impairs resistance acquisition, linking dNTP regulation to therapeutic resistance.