YTHDF3 Modulates EGFR/ATK/ERK/p21 Signaling Axis to Promote Cancer Progression and Osimertinib Resistance of Glioblastoma Cells

Anticancer Res. 2023 Dec;43(12):5485-5498. doi: 10.21873/anticanres.16751.

Abstract

Background/aim: Despite recent advances in EGFR-tyrosine kinase inhibitor (TKI) drugs for glioblastoma multiforme (GBM), intrinsic EGFR alterations in GBM have resulted in drug resistance and unsatisfactory clinical development of EGFR-TKIs. Determining the unknown mechanisms underlying EGFR-TKI drug resistance is an urgent, but unmet, medical need for GBM. Although several m6A RNA methylation regulators, such as reader YTHDF1/2, were recently predicted to be related to GBM recurrence, none was associated with resistance to the 3rd generation EGFR-TKI osimertinib.

Materials and methods: Osimertinib-resistant GBM cells (U87OSR) were established to ascertain the correlation between m6A expression and osimertinib resistance, prior to systemic analyses on m6A writers, erasers, and readers. YTHDF3-silencing was employed to reveal changes in IC50, cellular migration, cancer stemness, and p21-guided senescence in U87OSR cells. Signaling pathways and an in vivo xenograft model of U87OSR cells were investigated to delineate the influence of osimertinib-resistance and elevated YTHDF3 expression.

Results: YTHDF3 played a crucial role in inducing cellular proliferation, migration, and stemness in U87OSR GBM cells. Importantly, silencing of YTHDF3 markedly reduced the activation of certain signaling pathways, including EGFR- or ITGA7- AKT, and ERK in U87OSR cells. Our study also revealed the oncogenic function of YTHDF3 in inducing senescence escape via p21 down-regulation. In contrast, silencing of YTHDF3 resulted in increased p21 expression, senescence, and suppressed tumor growth in our osimertinib-resistant preclinical model.

Conclusion: Overall, our research underscores the novel potential of YTHDF3 as a new pharmacological target in GBM treatment, specifically for patients with osimertinib-resistant or refractory tumors.

Keywords: EGFR; GBM; Osimertinib; Osimertinib resistance; YTHDF3; p21; senescence; stemness.

MeSH terms

  • Aniline Compounds / pharmacology
  • Aniline Compounds / therapeutic use
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • ErbB Receptors / genetics
  • Glioblastoma* / drug therapy
  • Glioblastoma* / genetics
  • Glioblastoma* / metabolism
  • Humans
  • Lung Neoplasms* / pathology
  • Mutation
  • Protein Kinase Inhibitors / pharmacology
  • Protein Kinase Inhibitors / therapeutic use
  • Signal Transduction

Substances

  • Aniline Compounds
  • EGFR protein, human
  • ErbB Receptors
  • osimertinib
  • Protein Kinase Inhibitors
  • YTHDF3 protein, human