Jia Xiaoting, Tian Jingjie, Chen Pingping, Dong Jing, Li Lei, Chen Danyang, Zhang Jianlei, Liao Dongjiang, He Zhimin, Luo Kai
Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University; State Key Laboratory of Respiratory Disease, Guangzhou, Guangdong, China.
Hubei Jianghan Oilfield General Hospital, Qianjiang, Hubei, China.
Commun Biol. 2024 Dec 19;7(1):1649. doi: 10.1038/s42003-024-07339-3.
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.
不可避免的吉非替尼耐药是当前治疗中的最大瓶颈，其机制尚未完全明确。在此，我们观察到在对吉非替尼耐药的非小细胞肺癌（NSCLC）中，PFTK1（也称为CDK14）显著上调。并且PFTK1的上调与接受吉非替尼治疗的NSCLC患者的无进展生存期（PFS）呈负相关。进一步研究表明，吉非替尼可通过依赖DNMT3B抑制其启动子甲基化，从而显著促进PFTK1表达。功能获得和缺失实验表明，PFTK1失调显著增强了NSCLC对吉非替尼的耐药性。PFTK1与LRP6相互作用并激活Wnt/β-连环蛋白信号通路，以减弱吉非替尼诱导的细胞凋亡。此外，PFTK1的特异性共价抑制剂FMF-04-159-2在体外和体内均可逆转PFTK1对吉非替尼耐药的影响。因此，这些发现为吉非替尼耐药机制提供了新的见解，并提示PFTK1可作为NSCLC中吉非替尼治疗的靶点。
