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

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 m ⁶ A RNA methylation regulators, such as reader YTHDF1/2, were recently predicted to be related to GBM recurrence, none was associated with resistance to the 3 ^rd generation EGFR-TKI osimertinib.
Materials and Methods: Osimertinib-resistant GBM cells (U87 ^OSR ) were established to ascertain the correlation between m ⁶ A expression and osimertinib resistance, prior to systemic analyses on m ⁶ A writers, erasers, and readers. YTHDF3-silencing was employed to reveal changes in IC ₅₀ , cellular migration, cancer stemness, and p21-guided senescence in U87 ^OSR cells. Signaling pathways and an in vivo xenograft model of U87 ^OSR 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 U87 ^OSR GBM cells. Importantly, silencing of YTHDF3 markedly reduced the activation of certain signaling pathways, including EGFR- or ITGA7- AKT, and ERK in U87 ^OSR 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.
(Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)