Methylation-modulated PFTK1 Regulates Gefitinib Resistance Via Wnt/β-catenin Signaling in EGFR Mutant Non-small-cell Lung Cancer Cells

Overview

Journal Commun Biol

Specialty Biology

Date 2024 Dec 20

PMID 39702755

Authors

Xiaoting Jia

Jingjie Tian

Pingping Chen

Jing Dong

Lei Li

Danyang Chen

Jianlei Zhang

Dongjiang Liao

Zhimin He

Kai Luo

Affiliations

Soon will be listed here.

Abstract

Inevitable gefitinib resistance is the biggest bottleneck in current treatment and the mechanisms are not fully understood. Here, we observe that PFTK1 (also named CDK14) is significantly enhanced in NSCLC with gefitinib resistance. And the upregulation of PFTK1 is negatively associated with progression-free survival (PFS) in NSCLC patients who receive gefitinib treatment. Further study suggests that gefitinib can critically accelerate PFTK1 through suppressing its promoter methylation in a DNMT3B-dependent manner. Gain and loss of function assays demonstrate that desregulation of PFTK1 significantly enhances gefitinib resistance in NSCLC. PFTK1 interacts with LRP6 and activates Wnt/β-catenin signaling to attenuate gefitinib-induced cellular apoptosis. Moreover, FMF-04-159-2, a specific covalent inhibitor of PFTK1, can reverse the effect of PFTK1 on gefitinib resistance in vitro and in vivo. Consequently, these findings shed new light on the mechanism underlying gefitinib resistance, and suggest PFTK1 as a target for gefitinib treatment in NSCLC.

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