STAT3 inhibition suppresses adaptive survival of ALK-rearranged lung cancer cells through transcriptional modulation of apoptosis
Abstract Patients with advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer who are prescribed ALK-tyrosine kinase inhibitors (ALK-TKIs) rarely have complete responses, with residual tumors relapsing as heterogeneous resistant phenotypes. Herein, we investigated new therap...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2022-02-01
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| Series: | npj Precision Oncology |
| Online Access: | https://doi.org/10.1038/s41698-022-00254-y |
| _version_ | 1797643073462730752 |
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| author | Naohiro Yanagimura Shinji Takeuchi Koji Fukuda Sachiko Arai Azusa Tanimoto Akihiro Nishiyama Naohisa Ogo Hiroyuki Takahashi Akira Asai Satoshi Watanabe Toshiaki Kikuchi Seiji Yano |
| author_facet | Naohiro Yanagimura Shinji Takeuchi Koji Fukuda Sachiko Arai Azusa Tanimoto Akihiro Nishiyama Naohisa Ogo Hiroyuki Takahashi Akira Asai Satoshi Watanabe Toshiaki Kikuchi Seiji Yano |
| author_sort | Naohiro Yanagimura |
| collection | DOAJ |
| description | Abstract Patients with advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer who are prescribed ALK-tyrosine kinase inhibitors (ALK-TKIs) rarely have complete responses, with residual tumors relapsing as heterogeneous resistant phenotypes. Herein, we investigated new therapeutic strategies to reduce and eliminate residual tumors in the early treatment phase. Functional genomic screening using small guide RNA libraries showed that treatment-induced adaptive survival of ALK-rearranged lung cancer cells was predominantly dependent on STAT3 activity upon ALK inhibition. STAT3 inhibition effectively suppressed the adaptive survival of ALK-rearranged lung cancer cells by enhancing ALK inhibition-induced apoptosis. The combined effects were characterized by treatment-induced STAT3 dependence and transcriptional regulation of anti-apoptotic factor BCL-XL. In xenograft study, the combination of YHO-1701 (STAT3 inhibitor) and alectinib significantly suppressed tumor regrowth after treatment cessation with near tumor remission compared with alectinib alone. Hence, this study provides new insights into combined therapeutic strategies for patients with ALK-rearranged lung cancer. |
| first_indexed | 2024-03-11T14:09:23Z |
| format | Article |
| id | doaj.art-96cbee869e9e46158e3c0f9d71481295 |
| institution | Directory Open Access Journal |
| issn | 2397-768X |
| language | English |
| last_indexed | 2024-03-11T14:09:23Z |
| publishDate | 2022-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Precision Oncology |
| spelling | doaj.art-96cbee869e9e46158e3c0f9d714812952023-11-02T00:38:25ZengNature Portfolionpj Precision Oncology2397-768X2022-02-016111210.1038/s41698-022-00254-ySTAT3 inhibition suppresses adaptive survival of ALK-rearranged lung cancer cells through transcriptional modulation of apoptosisNaohiro Yanagimura0Shinji Takeuchi1Koji Fukuda2Sachiko Arai3Azusa Tanimoto4Akihiro Nishiyama5Naohisa Ogo6Hiroyuki Takahashi7Akira Asai8Satoshi Watanabe9Toshiaki Kikuchi10Seiji Yano11Division of Medical Oncology Cancer Research Institute, Kanazawa UniversityDivision of Medical Oncology Cancer Research Institute, Kanazawa UniversityDivision of Medical Oncology Cancer Research Institute, Kanazawa UniversityDivision of Medical Oncology Cancer Research Institute, Kanazawa UniversityDivision of Medical Oncology Cancer Research Institute, Kanazawa UniversityDivision of Medical Oncology Cancer Research Institute, Kanazawa UniversityCenter for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of ShizuokaCenter for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of ShizuokaCenter for Drug Discovery, Graduate School of Pharmaceutical Sciences, University of ShizuokaDepartment of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental SciencesDepartment of Respiratory Medicine and Infectious Diseases, Niigata University Graduate School of Medical and Dental SciencesDivision of Medical Oncology Cancer Research Institute, Kanazawa UniversityAbstract Patients with advanced anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer who are prescribed ALK-tyrosine kinase inhibitors (ALK-TKIs) rarely have complete responses, with residual tumors relapsing as heterogeneous resistant phenotypes. Herein, we investigated new therapeutic strategies to reduce and eliminate residual tumors in the early treatment phase. Functional genomic screening using small guide RNA libraries showed that treatment-induced adaptive survival of ALK-rearranged lung cancer cells was predominantly dependent on STAT3 activity upon ALK inhibition. STAT3 inhibition effectively suppressed the adaptive survival of ALK-rearranged lung cancer cells by enhancing ALK inhibition-induced apoptosis. The combined effects were characterized by treatment-induced STAT3 dependence and transcriptional regulation of anti-apoptotic factor BCL-XL. In xenograft study, the combination of YHO-1701 (STAT3 inhibitor) and alectinib significantly suppressed tumor regrowth after treatment cessation with near tumor remission compared with alectinib alone. Hence, this study provides new insights into combined therapeutic strategies for patients with ALK-rearranged lung cancer.https://doi.org/10.1038/s41698-022-00254-y |
| spellingShingle | Naohiro Yanagimura Shinji Takeuchi Koji Fukuda Sachiko Arai Azusa Tanimoto Akihiro Nishiyama Naohisa Ogo Hiroyuki Takahashi Akira Asai Satoshi Watanabe Toshiaki Kikuchi Seiji Yano STAT3 inhibition suppresses adaptive survival of ALK-rearranged lung cancer cells through transcriptional modulation of apoptosis npj Precision Oncology |
| title | STAT3 inhibition suppresses adaptive survival of ALK-rearranged lung cancer cells through transcriptional modulation of apoptosis |
| title_full | STAT3 inhibition suppresses adaptive survival of ALK-rearranged lung cancer cells through transcriptional modulation of apoptosis |
| title_fullStr | STAT3 inhibition suppresses adaptive survival of ALK-rearranged lung cancer cells through transcriptional modulation of apoptosis |
| title_full_unstemmed | STAT3 inhibition suppresses adaptive survival of ALK-rearranged lung cancer cells through transcriptional modulation of apoptosis |
| title_short | STAT3 inhibition suppresses adaptive survival of ALK-rearranged lung cancer cells through transcriptional modulation of apoptosis |
| title_sort | stat3 inhibition suppresses adaptive survival of alk rearranged lung cancer cells through transcriptional modulation of apoptosis |
| url | https://doi.org/10.1038/s41698-022-00254-y |
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