m6A regulators as predictive biomarkers for chemotherapy benefit and potential therapeutic targets for overcoming chemotherapy resistance in small-cell lung cancer

Abstract Small-cell lung cancer (SCLC) is a devastating subtype of lung cancer with few therapeutic options. Despite the advent of immunotherapy, platinum-based chemotherapy is still the irreplaceable first-line therapy for SCLCs. However, drug resistance will invariably occur in most patients and t...

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Autores principales:	Zhihui Zhang, Chaoqi Zhang, Zhaoyang Yang, Guochao Zhang, Peng Wu, Yuejun Luo, Qingpeng Zeng, Lide Wang, Qi Xue, Yi Zhang, Nan Sun, Jie He
Formato:	article
Lenguaje:	EN
Publicado:	BMC 2021
Materias:	Small-cell lung cancer m6A regulators Epigenetic modification Chemotherapy resistance Individualized medicine Diseases of the blood and blood-forming organs RC633-647.5 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/de7bfad1ceb74b3ea418b7cded854a63
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spelling	oai:doaj.org-article:de7bfad1ceb74b3ea418b7cded854a632021-11-14T12:05:39Zm6A regulators as predictive biomarkers for chemotherapy benefit and potential therapeutic targets for overcoming chemotherapy resistance in small-cell lung cancer10.1186/s13045-021-01173-41756-8722https://doaj.org/article/de7bfad1ceb74b3ea418b7cded854a632021-11-01T00:00:00Zhttps://doi.org/10.1186/s13045-021-01173-4https://doaj.org/toc/1756-8722Abstract Small-cell lung cancer (SCLC) is a devastating subtype of lung cancer with few therapeutic options. Despite the advent of immunotherapy, platinum-based chemotherapy is still the irreplaceable first-line therapy for SCLCs. However, drug resistance will invariably occur in most patients and the outcomes are heterogeneous. Therefore, clinically feasible classification strategies and potential therapeutic targets for overcoming chemotherapy resistance are urgently needed. N 6-methyladenosine (m6A) is a novel epigenetic decisive factor that is involved in tumor progression and drug resistance. However, almost nothing is known about m6A modification in SCLC. Here, we assessed 200 SCLC samples from patients who underwent chemotherapy from three different cohorts, including a validation cohort containing 71 cases with qPCR data and an independent cohort containing 79 cases with immunohistochemistry data (quantified as H-score). We systematically characterized the predictive landscape of m6A regulators in SCLC patients following with chemotherapy. Using the LASSO Cox model, we built a seven-regulator-based (ZCCHC4, IGF2BP3, ALKBH5, YTHDF3, METTL5, G3BP1, and RBMX) chemotherapy benefit predictive classifier (m6A score) and subsequently validated the classifier in two other cohorts. Time-dependent ROC and C-index analyses showed that the m6A score to possessed superior predictive power for chemotherapy benefit in comparison with other clinicopathological parameters. A multicohort multivariate analysis revealed that the m6A score is an independent factor that affects survival benefit across multiple cohorts. Our in vitro experimental results revealed that three regulators—ZCCHC4, G3BP1, and RBMX—may serve as promising novel therapeutic targets for overcoming chemoresistance in SCLCs. Our results, for the first time, demonstrate the predictive significance of m6A regulators for chemotherapy benefit, as well as their potential as therapeutic targets for overcoming chemotherapy resistance in SCLC patients. The m6A score was found to be a reliable prognostic tool that may help guide chemotherapy decisions for patients with SCLC.Zhihui ZhangChaoqi ZhangZhaoyang YangGuochao ZhangPeng WuYuejun LuoQingpeng ZengLide WangQi XueYi ZhangNan SunJie HeBMCarticleSmall-cell lung cancerm6A regulatorsEpigenetic modificationChemotherapy resistanceIndividualized medicineDiseases of the blood and blood-forming organsRC633-647.5Neoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENJournal of Hematology & Oncology, Vol 14, Iss 1, Pp 1-5 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Small-cell lung cancer m6A regulators Epigenetic modification Chemotherapy resistance Individualized medicine Diseases of the blood and blood-forming organs RC633-647.5 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	Small-cell lung cancer m6A regulators Epigenetic modification Chemotherapy resistance Individualized medicine Diseases of the blood and blood-forming organs RC633-647.5 Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Zhihui Zhang Chaoqi Zhang Zhaoyang Yang Guochao Zhang Peng Wu Yuejun Luo Qingpeng Zeng Lide Wang Qi Xue Yi Zhang Nan Sun Jie He m6A regulators as predictive biomarkers for chemotherapy benefit and potential therapeutic targets for overcoming chemotherapy resistance in small-cell lung cancer
description	Abstract Small-cell lung cancer (SCLC) is a devastating subtype of lung cancer with few therapeutic options. Despite the advent of immunotherapy, platinum-based chemotherapy is still the irreplaceable first-line therapy for SCLCs. However, drug resistance will invariably occur in most patients and the outcomes are heterogeneous. Therefore, clinically feasible classification strategies and potential therapeutic targets for overcoming chemotherapy resistance are urgently needed. N 6-methyladenosine (m6A) is a novel epigenetic decisive factor that is involved in tumor progression and drug resistance. However, almost nothing is known about m6A modification in SCLC. Here, we assessed 200 SCLC samples from patients who underwent chemotherapy from three different cohorts, including a validation cohort containing 71 cases with qPCR data and an independent cohort containing 79 cases with immunohistochemistry data (quantified as H-score). We systematically characterized the predictive landscape of m6A regulators in SCLC patients following with chemotherapy. Using the LASSO Cox model, we built a seven-regulator-based (ZCCHC4, IGF2BP3, ALKBH5, YTHDF3, METTL5, G3BP1, and RBMX) chemotherapy benefit predictive classifier (m6A score) and subsequently validated the classifier in two other cohorts. Time-dependent ROC and C-index analyses showed that the m6A score to possessed superior predictive power for chemotherapy benefit in comparison with other clinicopathological parameters. A multicohort multivariate analysis revealed that the m6A score is an independent factor that affects survival benefit across multiple cohorts. Our in vitro experimental results revealed that three regulators—ZCCHC4, G3BP1, and RBMX—may serve as promising novel therapeutic targets for overcoming chemoresistance in SCLCs. Our results, for the first time, demonstrate the predictive significance of m6A regulators for chemotherapy benefit, as well as their potential as therapeutic targets for overcoming chemotherapy resistance in SCLC patients. The m6A score was found to be a reliable prognostic tool that may help guide chemotherapy decisions for patients with SCLC.
format	article
author	Zhihui Zhang Chaoqi Zhang Zhaoyang Yang Guochao Zhang Peng Wu Yuejun Luo Qingpeng Zeng Lide Wang Qi Xue Yi Zhang Nan Sun Jie He
author_facet	Zhihui Zhang Chaoqi Zhang Zhaoyang Yang Guochao Zhang Peng Wu Yuejun Luo Qingpeng Zeng Lide Wang Qi Xue Yi Zhang Nan Sun Jie He
author_sort	Zhihui Zhang
title	m6A regulators as predictive biomarkers for chemotherapy benefit and potential therapeutic targets for overcoming chemotherapy resistance in small-cell lung cancer
title_short	m6A regulators as predictive biomarkers for chemotherapy benefit and potential therapeutic targets for overcoming chemotherapy resistance in small-cell lung cancer
title_full	m6A regulators as predictive biomarkers for chemotherapy benefit and potential therapeutic targets for overcoming chemotherapy resistance in small-cell lung cancer
title_fullStr	m6A regulators as predictive biomarkers for chemotherapy benefit and potential therapeutic targets for overcoming chemotherapy resistance in small-cell lung cancer
title_full_unstemmed	m6A regulators as predictive biomarkers for chemotherapy benefit and potential therapeutic targets for overcoming chemotherapy resistance in small-cell lung cancer
title_sort	m6a regulators as predictive biomarkers for chemotherapy benefit and potential therapeutic targets for overcoming chemotherapy resistance in small-cell lung cancer
publisher	BMC
publishDate	2021
url	https://doaj.org/article/de7bfad1ceb74b3ea418b7cded854a63
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m6A regulators as predictive biomarkers for chemotherapy benefit and potential therapeutic targets for overcoming chemotherapy resistance in small-cell lung cancer

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