Autocrine EGF and TGF‐α promote primary and acquired resistance to ALK/c‐Met kinase inhibitors in non‐small‐cell lung cancer
Abstract Drug resistance severely limits the clinical therapeutic value of molecularly targeted drugs. Growth factors gain a tremendous amount of focus due to the ability to promote drug resistance in non‐small‐cell lung cancer (NSCLC). However, whether tumor cells themselves can mediate drug resist...
| Main Authors: | , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2023-02-01
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| Series: | Pharmacology Research & Perspectives |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/prp2.1047 |
| _version_ | 1811165293601357824 |
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| author | Yueqin Wang Yu Zhang Ruiying Chen Xin Tian |
| author_facet | Yueqin Wang Yu Zhang Ruiying Chen Xin Tian |
| author_sort | Yueqin Wang |
| collection | DOAJ |
| description | Abstract Drug resistance severely limits the clinical therapeutic value of molecularly targeted drugs. Growth factors gain a tremendous amount of focus due to the ability to promote drug resistance in non‐small‐cell lung cancer (NSCLC). However, whether tumor cells themselves can mediate drug resistance by secreting growth factors needs further clarification. Here, we first screened growth factors to identify autocrine epidermal growth factor (EGF) and transforming growth factor alpha (TGF‐α) that caused primary resistance to the ALK inhibitor TAE684 in H3122 cells and the c‐MET‐specific inhibitor SGX‐523 in EBC‐1 cells. Next, we discovered increased autocrine production of EGF and TGF‐α in established acquired resistant H3122/TR and EBC‐1/SR cells. Importantly, overexpression of EGF and TGF‐α in two NSCLC cell lines produced resistance to TAE684 and SGX‐523. Clinically, NSCLC patients with high expression of EGF and TGF‐α developed primary resistance to crizotinib. Mechanistically, autocrine EGF and TGF‐α activated EGFR signaling pathways to survive targeted c‐Met and ALK inhibition. Furthermore, combined treatment with gefitinib circumvented EGF‐ and TGF‐α‐mediated primary and acquired resistance to TAE684/SGX‐523. Taken together, these results suggested increased autocrine EGF and TGF‐α conferred primary and acquired resistance to ALK/c‐Met kinase inhibitors in NSCLC. |
| first_indexed | 2024-04-10T15:34:55Z |
| format | Article |
| id | doaj.art-cb7867465caf4540acda978b1bc00a57 |
| institution | Directory Open Access Journal |
| issn | 2052-1707 |
| language | English |
| last_indexed | 2024-04-10T15:34:55Z |
| publishDate | 2023-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Pharmacology Research & Perspectives |
| spelling | doaj.art-cb7867465caf4540acda978b1bc00a572023-02-13T07:58:31ZengWileyPharmacology Research & Perspectives2052-17072023-02-01111n/an/a10.1002/prp2.1047Autocrine EGF and TGF‐α promote primary and acquired resistance to ALK/c‐Met kinase inhibitors in non‐small‐cell lung cancerYueqin Wang0Yu Zhang1Ruiying Chen2Xin Tian3Department of Pharmacy The First Affiliated Hospital of Zhengzhou University Zhengzhou ChinaDepartment of Pharmacy The First Affiliated Hospital of Zhengzhou University Zhengzhou ChinaDepartment of Respiratory medicine The First Affiliated Hospital of Zhengzhou University Zhengzhou ChinaDepartment of Pharmacy The First Affiliated Hospital of Zhengzhou University Zhengzhou ChinaAbstract Drug resistance severely limits the clinical therapeutic value of molecularly targeted drugs. Growth factors gain a tremendous amount of focus due to the ability to promote drug resistance in non‐small‐cell lung cancer (NSCLC). However, whether tumor cells themselves can mediate drug resistance by secreting growth factors needs further clarification. Here, we first screened growth factors to identify autocrine epidermal growth factor (EGF) and transforming growth factor alpha (TGF‐α) that caused primary resistance to the ALK inhibitor TAE684 in H3122 cells and the c‐MET‐specific inhibitor SGX‐523 in EBC‐1 cells. Next, we discovered increased autocrine production of EGF and TGF‐α in established acquired resistant H3122/TR and EBC‐1/SR cells. Importantly, overexpression of EGF and TGF‐α in two NSCLC cell lines produced resistance to TAE684 and SGX‐523. Clinically, NSCLC patients with high expression of EGF and TGF‐α developed primary resistance to crizotinib. Mechanistically, autocrine EGF and TGF‐α activated EGFR signaling pathways to survive targeted c‐Met and ALK inhibition. Furthermore, combined treatment with gefitinib circumvented EGF‐ and TGF‐α‐mediated primary and acquired resistance to TAE684/SGX‐523. Taken together, these results suggested increased autocrine EGF and TGF‐α conferred primary and acquired resistance to ALK/c‐Met kinase inhibitors in NSCLC.https://doi.org/10.1002/prp2.1047acquired resistanceautocrine growth factornon‐small‐cell lung cancerprimary resistance |
| spellingShingle | Yueqin Wang Yu Zhang Ruiying Chen Xin Tian Autocrine EGF and TGF‐α promote primary and acquired resistance to ALK/c‐Met kinase inhibitors in non‐small‐cell lung cancer Pharmacology Research & Perspectives acquired resistance autocrine growth factor non‐small‐cell lung cancer primary resistance |
| title | Autocrine EGF and TGF‐α promote primary and acquired resistance to ALK/c‐Met kinase inhibitors in non‐small‐cell lung cancer |
| title_full | Autocrine EGF and TGF‐α promote primary and acquired resistance to ALK/c‐Met kinase inhibitors in non‐small‐cell lung cancer |
| title_fullStr | Autocrine EGF and TGF‐α promote primary and acquired resistance to ALK/c‐Met kinase inhibitors in non‐small‐cell lung cancer |
| title_full_unstemmed | Autocrine EGF and TGF‐α promote primary and acquired resistance to ALK/c‐Met kinase inhibitors in non‐small‐cell lung cancer |
| title_short | Autocrine EGF and TGF‐α promote primary and acquired resistance to ALK/c‐Met kinase inhibitors in non‐small‐cell lung cancer |
| title_sort | autocrine egf and tgf α promote primary and acquired resistance to alk c met kinase inhibitors in non small cell lung cancer |
| topic | acquired resistance autocrine growth factor non‐small‐cell lung cancer primary resistance |
| url | https://doi.org/10.1002/prp2.1047 |
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