Methylation-modulated PFTK1 regulates gefitinib resistance via Wnt/β-catenin signaling in EGFR mutant non-small-cell lung cancer cells
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 wit...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-12-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-024-07339-3 |
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| author | Xiaoting Jia Jingjie Tian Pingping Chen Jing Dong Lei Li Danyang Chen Jianlei Zhang Dongjiang Liao Zhimin He Kai Luo |
| author_facet | Xiaoting Jia Jingjie Tian Pingping Chen Jing Dong Lei Li Danyang Chen Jianlei Zhang Dongjiang Liao Zhimin He Kai Luo |
| author_sort | Xiaoting Jia |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-84c0cc15b9414cc6b5e9089f7f4336bb |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-84c0cc15b9414cc6b5e9089f7f4336bb2024-12-22T12:41:52ZengNature PortfolioCommunications Biology2399-36422024-12-017111210.1038/s42003-024-07339-3Methylation-modulated PFTK1 regulates gefitinib resistance via Wnt/β-catenin signaling in EGFR mutant non-small-cell lung cancer cellsXiaoting Jia0Jingjie Tian1Pingping Chen2Jing Dong3Lei Li4Danyang Chen5Jianlei Zhang6Dongjiang Liao7Zhimin He8Kai Luo9Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University; State Key Laboratory of Respiratory DiseaseHubei Jianghan Oilfield General HospitalGuangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University; State Key Laboratory of Respiratory DiseaseZhuhai People’s HospitalGuangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University; State Key Laboratory of Respiratory DiseaseGuangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University; State Key Laboratory of Respiratory DiseaseGuangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University; State Key Laboratory of Respiratory DiseaseGuangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University; State Key Laboratory of Respiratory DiseaseGuangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University; State Key Laboratory of Respiratory DiseaseGuangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University; State Key Laboratory of Respiratory DiseaseAbstract 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.https://doi.org/10.1038/s42003-024-07339-3 |
| spellingShingle | Xiaoting Jia Jingjie Tian Pingping Chen Jing Dong Lei Li Danyang Chen Jianlei Zhang Dongjiang Liao Zhimin He Kai Luo Methylation-modulated PFTK1 regulates gefitinib resistance via Wnt/β-catenin signaling in EGFR mutant non-small-cell lung cancer cells Communications Biology |
| title | Methylation-modulated PFTK1 regulates gefitinib resistance via Wnt/β-catenin signaling in EGFR mutant non-small-cell lung cancer cells |
| title_full | Methylation-modulated PFTK1 regulates gefitinib resistance via Wnt/β-catenin signaling in EGFR mutant non-small-cell lung cancer cells |
| title_fullStr | Methylation-modulated PFTK1 regulates gefitinib resistance via Wnt/β-catenin signaling in EGFR mutant non-small-cell lung cancer cells |
| title_full_unstemmed | Methylation-modulated PFTK1 regulates gefitinib resistance via Wnt/β-catenin signaling in EGFR mutant non-small-cell lung cancer cells |
| title_short | Methylation-modulated PFTK1 regulates gefitinib resistance via Wnt/β-catenin signaling in EGFR mutant non-small-cell lung cancer cells |
| title_sort | methylation modulated pftk1 regulates gefitinib resistance via wnt β catenin signaling in egfr mutant non small cell lung cancer cells |
| url | https://doi.org/10.1038/s42003-024-07339-3 |
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