MED12 mutation induces RTK inhibitor resistance in NSCLC via MEK/ERK pathway activation by inflammatory cytokines
Abstract Non-small cell lung cancer (NSCLC) is frequently associated with mutations in receptor tyrosine kinases (RTKs), such as EGFR and ALK. While RTK inhibitors (RTKIs) have proven effective in treating patients with specific RTK mutations, the emergence of resistance to these therapies remains a...
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| Format: | Article |
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Springer
2025-08-01
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| Series: | Cellular and Molecular Life Sciences |
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| Online Access: | https://doi.org/10.1007/s00018-025-05791-w |
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| author | Hyun-Min Ryu Deokhoon Kim Jun Young Choi Shinkyo Yoon Ho-Su Lee Ji Eun Park Eunjin Lee Yunkyung Sung Chang Hoon Lee Eun-Young Lee Wanlim Kim Seyoung Seo Sang-We Kim Kang-Seo Park Dae Ho Lee |
| author_facet | Hyun-Min Ryu Deokhoon Kim Jun Young Choi Shinkyo Yoon Ho-Su Lee Ji Eun Park Eunjin Lee Yunkyung Sung Chang Hoon Lee Eun-Young Lee Wanlim Kim Seyoung Seo Sang-We Kim Kang-Seo Park Dae Ho Lee |
| author_sort | Hyun-Min Ryu |
| collection | DOAJ |
| description | Abstract Non-small cell lung cancer (NSCLC) is frequently associated with mutations in receptor tyrosine kinases (RTKs), such as EGFR and ALK. While RTK inhibitors (RTKIs) have proven effective in treating patients with specific RTK mutations, the emergence of resistance to these therapies remains a significant clinical obstacle. As such, there is still an unmet need for the identification of new biomarkers that can predict resistance to RTK inhibitors in clinical use. In the present study, we demonstrate that MED12 mutations are a key driver of RTKi resistance in NSCLC cells. This resistance is mediated through the release of inflammatory cytokines triggered by MED12 degradation. Notably, we observed that of the two major downstream signaling pathways activated by inflammatory cytokines, only the MEK/ERK pathway was upregulated, while the PI3K/AKT pathway was unaffected in MED12 knock-out (KO) cells. The degradation of MED12 results in the dissociation of the MED12 complex, which subsequently leads to YAP phosphorylation. This phosphorylated YAP increases PTEN expression by inhibiting miR-29, thereby suppressing the PI3K/AKT signaling pathway. Importantly, treatment with trametinib, a MEK inhibitor, effectively suppressed tumor growth in MED12KO NSCLC cells and in xenograft models derived from these cells. These findings suggest that targeting the MEK/ERK signaling pathway, such as with trametinib, may provide a viable strategy to overcome RTKi resistance in MED12-mutant NSCLC. Furthermore, MED12 is identified as a crucial biomarker and potential therapeutic target for overcoming RTKi resistance. |
| format | Article |
| id | doaj-art-4c12d97771fa49aaaa812e935ef066e8 |
| institution | Kabale University |
| issn | 1420-9071 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Springer |
| record_format | Article |
| series | Cellular and Molecular Life Sciences |
| spelling | doaj-art-4c12d97771fa49aaaa812e935ef066e82025-08-24T11:12:37ZengSpringerCellular and Molecular Life Sciences1420-90712025-08-0182112010.1007/s00018-025-05791-wMED12 mutation induces RTK inhibitor resistance in NSCLC via MEK/ERK pathway activation by inflammatory cytokinesHyun-Min Ryu0Deokhoon Kim1Jun Young Choi2Shinkyo Yoon3Ho-Su Lee4Ji Eun Park5Eunjin Lee6Yunkyung Sung7Chang Hoon Lee8Eun-Young Lee9Wanlim Kim10Seyoung Seo11Sang-We Kim12Kang-Seo Park13Dae Ho Lee14Department of Oncology, Asan Medical Center, University of Ulsan, College of MedicineDepartment of Pathology, Asan Medical Center, University of Ulsan College of MedicineDepartment of Oncology, Asan Medical Center, University of Ulsan, College of MedicineDepartment of Oncology, Asan Medical Center, University of Ulsan, College of MedicineDepartment of Biochemistry and Molecular Biology, University of Ulsan College of MedicineDepartment of Radiology and Research Institute of Radiology, College of Medicine, University of Ulsan, Asan Medical CenterDepartment of Oncology, Asan Medical Center, University of Ulsan, College of MedicineDepartment of Oncology, Asan Medical Center, University of Ulsan, College of MedicineSCBIO IncDepartment of Biochemistry College of medicine, Soonchunhyang UniversityDepartment of Orthopaedic Surgery, Asan Medical Center, University of Ulsan College of MedicineDepartment of Oncology, Asan Medical Center, University of Ulsan, College of MedicineDepartment of Oncology, Asan Medical Center, University of Ulsan, College of MedicineDepartment of Oncology, Asan Medical Center, University of Ulsan, College of MedicineDepartment of Oncology, Asan Medical Center, University of Ulsan, College of MedicineAbstract Non-small cell lung cancer (NSCLC) is frequently associated with mutations in receptor tyrosine kinases (RTKs), such as EGFR and ALK. While RTK inhibitors (RTKIs) have proven effective in treating patients with specific RTK mutations, the emergence of resistance to these therapies remains a significant clinical obstacle. As such, there is still an unmet need for the identification of new biomarkers that can predict resistance to RTK inhibitors in clinical use. In the present study, we demonstrate that MED12 mutations are a key driver of RTKi resistance in NSCLC cells. This resistance is mediated through the release of inflammatory cytokines triggered by MED12 degradation. Notably, we observed that of the two major downstream signaling pathways activated by inflammatory cytokines, only the MEK/ERK pathway was upregulated, while the PI3K/AKT pathway was unaffected in MED12 knock-out (KO) cells. The degradation of MED12 results in the dissociation of the MED12 complex, which subsequently leads to YAP phosphorylation. This phosphorylated YAP increases PTEN expression by inhibiting miR-29, thereby suppressing the PI3K/AKT signaling pathway. Importantly, treatment with trametinib, a MEK inhibitor, effectively suppressed tumor growth in MED12KO NSCLC cells and in xenograft models derived from these cells. These findings suggest that targeting the MEK/ERK signaling pathway, such as with trametinib, may provide a viable strategy to overcome RTKi resistance in MED12-mutant NSCLC. Furthermore, MED12 is identified as a crucial biomarker and potential therapeutic target for overcoming RTKi resistance.https://doi.org/10.1007/s00018-025-05791-wNSCLCMED12 mutationDrug resistanceReceptor tyrosine kinase inhibitorMEK inhibitor |
| spellingShingle | Hyun-Min Ryu Deokhoon Kim Jun Young Choi Shinkyo Yoon Ho-Su Lee Ji Eun Park Eunjin Lee Yunkyung Sung Chang Hoon Lee Eun-Young Lee Wanlim Kim Seyoung Seo Sang-We Kim Kang-Seo Park Dae Ho Lee MED12 mutation induces RTK inhibitor resistance in NSCLC via MEK/ERK pathway activation by inflammatory cytokines Cellular and Molecular Life Sciences NSCLC MED12 mutation Drug resistance Receptor tyrosine kinase inhibitor MEK inhibitor |
| title | MED12 mutation induces RTK inhibitor resistance in NSCLC via MEK/ERK pathway activation by inflammatory cytokines |
| title_full | MED12 mutation induces RTK inhibitor resistance in NSCLC via MEK/ERK pathway activation by inflammatory cytokines |
| title_fullStr | MED12 mutation induces RTK inhibitor resistance in NSCLC via MEK/ERK pathway activation by inflammatory cytokines |
| title_full_unstemmed | MED12 mutation induces RTK inhibitor resistance in NSCLC via MEK/ERK pathway activation by inflammatory cytokines |
| title_short | MED12 mutation induces RTK inhibitor resistance in NSCLC via MEK/ERK pathway activation by inflammatory cytokines |
| title_sort | med12 mutation induces rtk inhibitor resistance in nsclc via mek erk pathway activation by inflammatory cytokines |
| topic | NSCLC MED12 mutation Drug resistance Receptor tyrosine kinase inhibitor MEK inhibitor |
| url | https://doi.org/10.1007/s00018-025-05791-w |
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