Adaptive resistance to lorlatinib via EGFR signaling in ALK-rearranged lung cancer
Abstract Anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors rarely elicit complete responses in patients with advanced ALK-rearranged non-small cell lung cancer (NSCLC), as a small population of tumor cells survives due to adaptive resistance. Therefore, we focused on the mechanisms underly...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-01-01
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| Series: | npj Precision Oncology |
| Online Access: | https://doi.org/10.1038/s41698-023-00350-7 |
| _version_ | 1797641405457235968 |
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| author | Yuki Katayama Tadaaki Yamada Keiko Tanimura Shinsaku Tokuda Kenji Morimoto Soichi Hirai Yohei Matsui Ryota Nakamura Masaki Ishida Hayato Kawachi Kazue Yoneda Kazutaka Hosoya Takahiro Tsuji Hiroaki Ozasa Akihiro Yoshimura Masahiro Iwasaku Young Hak Kim Mano Horinaka Toshiyuki Sakai Takahiro Utsumi Shinsuke Shiotsu Takayuki Takeda Ryohei Katayama Koichi Takayama |
| author_facet | Yuki Katayama Tadaaki Yamada Keiko Tanimura Shinsaku Tokuda Kenji Morimoto Soichi Hirai Yohei Matsui Ryota Nakamura Masaki Ishida Hayato Kawachi Kazue Yoneda Kazutaka Hosoya Takahiro Tsuji Hiroaki Ozasa Akihiro Yoshimura Masahiro Iwasaku Young Hak Kim Mano Horinaka Toshiyuki Sakai Takahiro Utsumi Shinsuke Shiotsu Takayuki Takeda Ryohei Katayama Koichi Takayama |
| author_sort | Yuki Katayama |
| collection | DOAJ |
| description | Abstract Anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors rarely elicit complete responses in patients with advanced ALK-rearranged non-small cell lung cancer (NSCLC), as a small population of tumor cells survives due to adaptive resistance. Therefore, we focused on the mechanisms underlying adaptive resistance to lorlatinib and therapeutic strategies required to overcome them. We found that epidermal growth factor receptor (EGFR) signaling was involved in the adaptive resistance to lorlatinib in ALK-rearranged NSCLC, activation of which was induced by heparin-binding EGF-like growth factor production via c-Jun activation. EGFR inhibition halted ALK-rearranged lung cancer cell proliferation by enhancing ALK inhibition-induced apoptosis via suppression of Bcl-xL. Xenograft models showed that the combination of EGFR inhibitor and lorlatinib considerably suppressed tumor regrowth following cessation of these treatments. This study provides new insights regarding tumor evolution due to EGFR signaling after lorlatinib treatment and the development of combined therapeutic strategies for ALK-rearranged lung cancer. |
| first_indexed | 2024-03-11T13:45:11Z |
| format | Article |
| id | doaj.art-583207af794a452d86780039dd00b9de |
| institution | Directory Open Access Journal |
| issn | 2397-768X |
| language | English |
| last_indexed | 2024-03-11T13:45:11Z |
| publishDate | 2023-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Precision Oncology |
| spelling | doaj.art-583207af794a452d86780039dd00b9de2023-11-02T10:37:50ZengNature Portfolionpj Precision Oncology2397-768X2023-01-017111310.1038/s41698-023-00350-7Adaptive resistance to lorlatinib via EGFR signaling in ALK-rearranged lung cancerYuki Katayama0Tadaaki Yamada1Keiko Tanimura2Shinsaku Tokuda3Kenji Morimoto4Soichi Hirai5Yohei Matsui6Ryota Nakamura7Masaki Ishida8Hayato Kawachi9Kazue Yoneda10Kazutaka Hosoya11Takahiro Tsuji12Hiroaki Ozasa13Akihiro Yoshimura14Masahiro Iwasaku15Young Hak Kim16Mano Horinaka17Toshiyuki Sakai18Takahiro Utsumi19Shinsuke Shiotsu20Takayuki Takeda21Ryohei Katayama22Koichi Takayama23Department of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of MedicineDepartment of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of MedicineDepartment of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of MedicineDepartment of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of MedicineDepartment of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of MedicineDepartment of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of MedicineDepartment of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of MedicineDepartment of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of MedicineDepartment of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of MedicineDepartment of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of MedicineSecond Department of Surgery, University of Occupational and Environmental HealthDepartment of Respiratory Medicine, Graduate School of Medicine, Kyoto UniversityDepartment of Respiratory Medicine, Graduate School of Medicine, Kyoto UniversityDepartment of Respiratory Medicine, Graduate School of Medicine, Kyoto UniversityDepartment of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of MedicineDepartment of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of MedicineDepartment of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of MedicineDepartment of Drug Discovery Medicine, Graduate School of Medical Science, Kyoto Prefectural University of MedicineDepartment of Drug Discovery Medicine, Graduate School of Medical Science, Kyoto Prefectural University of MedicineDivision of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer ResearchDepartment of Respiratory Medicine, Japanese Red Cross Kyoto Daiichi HospitalDepartment of Respiratory Medicine, Japanese Red Cross Kyoto Daini HospitalDivision of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer ResearchDepartment of Pulmonary Medicine, Graduate School of Medical Science, Kyoto Prefectural University of MedicineAbstract Anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitors rarely elicit complete responses in patients with advanced ALK-rearranged non-small cell lung cancer (NSCLC), as a small population of tumor cells survives due to adaptive resistance. Therefore, we focused on the mechanisms underlying adaptive resistance to lorlatinib and therapeutic strategies required to overcome them. We found that epidermal growth factor receptor (EGFR) signaling was involved in the adaptive resistance to lorlatinib in ALK-rearranged NSCLC, activation of which was induced by heparin-binding EGF-like growth factor production via c-Jun activation. EGFR inhibition halted ALK-rearranged lung cancer cell proliferation by enhancing ALK inhibition-induced apoptosis via suppression of Bcl-xL. Xenograft models showed that the combination of EGFR inhibitor and lorlatinib considerably suppressed tumor regrowth following cessation of these treatments. This study provides new insights regarding tumor evolution due to EGFR signaling after lorlatinib treatment and the development of combined therapeutic strategies for ALK-rearranged lung cancer.https://doi.org/10.1038/s41698-023-00350-7 |
| spellingShingle | Yuki Katayama Tadaaki Yamada Keiko Tanimura Shinsaku Tokuda Kenji Morimoto Soichi Hirai Yohei Matsui Ryota Nakamura Masaki Ishida Hayato Kawachi Kazue Yoneda Kazutaka Hosoya Takahiro Tsuji Hiroaki Ozasa Akihiro Yoshimura Masahiro Iwasaku Young Hak Kim Mano Horinaka Toshiyuki Sakai Takahiro Utsumi Shinsuke Shiotsu Takayuki Takeda Ryohei Katayama Koichi Takayama Adaptive resistance to lorlatinib via EGFR signaling in ALK-rearranged lung cancer npj Precision Oncology |
| title | Adaptive resistance to lorlatinib via EGFR signaling in ALK-rearranged lung cancer |
| title_full | Adaptive resistance to lorlatinib via EGFR signaling in ALK-rearranged lung cancer |
| title_fullStr | Adaptive resistance to lorlatinib via EGFR signaling in ALK-rearranged lung cancer |
| title_full_unstemmed | Adaptive resistance to lorlatinib via EGFR signaling in ALK-rearranged lung cancer |
| title_short | Adaptive resistance to lorlatinib via EGFR signaling in ALK-rearranged lung cancer |
| title_sort | adaptive resistance to lorlatinib via egfr signaling in alk rearranged lung cancer |
| url | https://doi.org/10.1038/s41698-023-00350-7 |
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