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

Hsun-Hua Lee1,2,3,4,5, Ching-Chuan Hsieh6, Cheng-Chih Chang6

  • 1Department of Neurology, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan, R.O.C.

Anticancer Research
|November 29, 2023
PubMed
Abstract

Insights

YTHDF3 promotes glioblastoma multiforme (GBM) resistance to osimertinib by driving proliferation, migration, and senescence escape. Silencing YTHDF3 suppresses tumor growth, highlighting it as a potential therapeutic target for resistant GBM.

Area of Science:

  • Oncology
  • Molecular Biology
  • Epigenetics

Background:

  • Glioblastoma multiforme (GBM) exhibits intrinsic resistance to EGFR-tyrosine kinase inhibitors (TKIs), including osimertinib.
  • Mechanisms underlying EGFR-TKI resistance in GBM remain largely unknown, representing a significant unmet medical need.
  • While m6A RNA methylation regulators are implicated in GBM recurrence, their role in osimertinib resistance is unexplored.

Purpose of the Study:

  • To investigate the role of m6A RNA methylation regulators in osimertinib resistance in GBM.
  • To determine the specific function of YTHDF3 in mediating resistance to the third-generation EGFR-TKI, osimertinib.
  • To explore YTHDF3 as a potential therapeutic target for osimertinib-resistant GBM.

Main Methods:

  • Established osimertinib-resistant GBM cell lines (U87OSR).
  • Utilized YTHDF3-silencing to assess effects on IC50, migration, stemness, and p21-guided senescence.
  • Investigated signaling pathways (EGFR, ITGA7, AKT, ERK) and conducted in vivo xenograft studies.

Main Results:

  • YTHDF3 significantly promotes proliferation, migration, and stemness in osimertinib-resistant GBM cells.
  • Silencing YTHDF3 reduces activation of EGFR, ITGA7, AKT, and ERK signaling pathways.
  • YTHDF3 contributes to senescence escape via p21 downregulation; its silencing increases p21, induces senescence, and suppresses tumor growth.

Conclusions:

  • YTHDF3 plays a critical oncogenic role in promoting osimertinib resistance in GBM.
  • Targeting YTHDF3 presents a novel therapeutic strategy for patients with osimertinib-resistant or refractory GBM.
  • This study identifies YTHDF3 as a promising pharmacological target for overcoming EGFR-TKI resistance in glioblastoma.
Keywords:
EGFRGBMOsimertinibOsimertinib resistanceYTHDF3p21senescencestemness

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