{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T02:40:39Z","timestamp":1787020839889,"version":"build-2736575974"},"reference-count":9,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,11,10]],"date-time":"2021-11-10T00:00:00Z","timestamp":1636502400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,11,10]],"date-time":"2021-11-10T00:00:00Z","timestamp":1636502400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"CAMS Innovation Fund for Medical Sciences","award":["2017-I2M-1-005"],"award-info":[{"award-number":["2017-I2M-1-005"]}]},{"DOI":"10.13039\/501100012226","name":"Fundamental Research Funds for the Central Universities","doi-asserted-by":"publisher","award":["3332018070"],"award-info":[{"award-number":["3332018070"]}],"id":[{"id":"10.13039\/501100012226","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Key Basic Research Development Plan","award":["2018YFC1312105"],"award-info":[{"award-number":["2018YFC1312105"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Hematol Oncol"],"published-print":{"date-parts":[[2021,12]]},"abstract":"Abstract<\/jats:title>\n \n 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 N<\/jats:italic>\n 6<\/jats:sup>\n -methyladenosine (m\n 6<\/jats:sup>\n A) is a novel epigenetic decisive factor that is involved in tumor progression and drug resistance. However, almost nothing is known about m\n 6<\/jats:sup>\n A 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 m\n 6<\/jats:sup>\n A regulators in SCLC patients following with chemotherapy. Using the LASSO Cox model, we built a seven-regulator-based (\n ZCCHC4<\/jats:italic>\n ,\n IGF2BP3<\/jats:italic>\n ,\n ALKBH5<\/jats:italic>\n ,\n YTHDF3<\/jats:italic>\n ,\n METTL5<\/jats:italic>\n ,\n G3BP1<\/jats:italic>\n , and\n RBMX<\/jats:italic>\n ) chemotherapy benefit predictive classifier (m\n 6<\/jats:sup>\n A score) and subsequently validated the classifier in two other cohorts. Time-dependent ROC and C-index analyses showed that the m\n 6<\/jats:sup>\n A score to possessed superior predictive power for chemotherapy benefit in comparison with other clinicopathological parameters. A multicohort multivariate analysis revealed that the m\n 6<\/jats:sup>\n A score is an independent factor that affects survival benefit across multiple cohorts. Our in vitro experimental results revealed that three regulators\u2014ZCCHC4, G3BP1, and RBMX\u2014may serve as promising novel therapeutic targets for overcoming chemoresistance in SCLCs. Our results, for the first time, demonstrate the predictive significance of m\n 6<\/jats:sup>\n A regulators for chemotherapy benefit, as well as their potential as therapeutic targets for overcoming chemotherapy resistance in SCLC patients. The m\n 6<\/jats:sup>\n A score was found to be a reliable prognostic tool that may help guide chemotherapy decisions for patients with SCLC.\n <\/jats:p>","DOI":"10.1186\/s13045-021-01173-4","type":"journal-article","created":{"date-parts":[[2021,11,10]],"date-time":"2021-11-10T07:12:12Z","timestamp":1636528332000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":63,"title":["m6A regulators as predictive biomarkers for chemotherapy benefit and potential therapeutic targets for overcoming chemotherapy resistance in small-cell lung cancer"],"prefix":"10.1186","volume":"14","author":[{"given":"Zhihui","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chaoqi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoyang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guochao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuejun","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingpeng","family":"Zeng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lide","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Xue","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0285-5403","authenticated-orcid":false,"given":"Jie","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,11,10]]},"reference":[{"key":"1173_CR1","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","volume":"71","author":"H Sung","year":"2021","unstructured":"Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality Worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209\u201349.","journal-title":"CA Cancer J Clin"},{"key":"1173_CR2","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1186\/s13045-021-01121-2","volume":"14","author":"U Majeed","year":"2021","unstructured":"Majeed U, Manochakian R, Zhao Y, Lou Y. Targeted therapy in advanced non-small cell lung cancer: current advances and future trends. J Hematol Oncol. 2021;14:108.","journal-title":"J Hematol Oncol"},{"key":"1173_CR3","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1186\/s13045-019-0745-2","volume":"12","author":"DH Owen","year":"2019","unstructured":"Owen DH, Giffin MJ, Bailis JM, Smit MD, Carbone DP, He K. DLL3: an emerging target in small cell lung cancer. J Hematol Oncol. 2019;12:61.","journal-title":"J Hematol Oncol"},{"key":"1173_CR4","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1038\/s41572-020-00235-0","volume":"7","author":"CM Rudin","year":"2021","unstructured":"Rudin CM, Brambilla E, Faivre-Finn C, Sage J. Small-cell lung cancer. Nat Rev Dis Primers. 2021;7:3.","journal-title":"Nat Rev Dis Primers"},{"key":"1173_CR5","doi-asserted-by":"publisher","first-page":"300","DOI":"10.1038\/s41571-019-0316-z","volume":"17","author":"WT Iams","year":"2020","unstructured":"Iams WT, Porter J, Horn L. Immunotherapeutic approaches for small-cell lung cancer. Nat Rev Clin Oncol. 2020;17:300\u201312.","journal-title":"Nat Rev Clin Oncol"},{"key":"1173_CR6","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1186\/s13045-019-0736-3","volume":"12","author":"S Yang","year":"2019","unstructured":"Yang S, Zhang Z, Wang Q. Emerging therapies for small cell lung cancer. J Hematol Oncol. 2019;12:47.","journal-title":"J Hematol Oncol"},{"key":"1173_CR7","doi-asserted-by":"publisher","first-page":"270","DOI":"10.1016\/j.ccell.2020.02.004","volume":"37","author":"H Huang","year":"2020","unstructured":"Huang H, Weng H, Chen J. m(6)A modification in coding and non-coding RNAs: roles and therapeutic implications in cancer. Cancer Cell. 2020;37:270\u201388.","journal-title":"Cancer Cell"},{"key":"1173_CR8","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1186\/s13045-020-00872-8","volume":"13","author":"Y Zhao","year":"2020","unstructured":"Zhao Y, Shi Y, Shen H, Xie W. m(6)A-binding proteins: the emerging crucial performers in epigenetics. J Hematol Oncol. 2020;13:35.","journal-title":"J Hematol Oncol"},{"key":"1173_CR9","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2020.11.006","author":"P Khan","year":"2020","unstructured":"Khan P, Siddiqui JA, Maurya SK, Lakshmanan I, Jain M, Ganti AK, et al. Epigenetic landscape of small cell lung cancer: small image of a giant recalcitrant disease. Semin Cancer Biol. 2020. https:\/\/doi.org\/10.1016\/j.semcancer.2020.11.006.","journal-title":"Semin Cancer Biol."}],"container-title":["Journal of Hematology & Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13045-021-01173-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s13045-021-01173-4\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s13045-021-01173-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,10]],"date-time":"2021-11-10T07:14:24Z","timestamp":1636528464000},"score":1,"resource":{"primary":{"URL":"https:\/\/jhoonline.biomedcentral.com\/articles\/10.1186\/s13045-021-01173-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,10]]},"references-count":9,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["1173"],"URL":"https:\/\/doi.org\/10.1186\/s13045-021-01173-4","relation":{},"ISSN":["1756-8722"],"issn-type":[{"value":"1756-8722","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,10]]},"assertion":[{"value":"6 August 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 September 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 November 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This study was approved by the Ethics Committee of the Cancer Hospital of the Chinese Academy of Medical Sciences. Due to retrospective nature of this study, the requirement for informed consent was waived. This work was conducted in compliance with the Declaration of Helsinki.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"The authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"190"}}