{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,6]],"date-time":"2026-11-06T21:55:29Z","timestamp":1794002129942,"version":"4.8.0"},"reference-count":46,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T00:00:00Z","timestamp":1787875200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"vor","delay-in-days":4,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82472927"],"award-info":[{"award-number":["82472927"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Transl Med"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Neuroendocrine transformation of epidermal growth factor receptor-mutant lung adenocarcinoma (EGFR\n                      <jats:sub>m<\/jats:sub>\n                      LUAD) represents a significant mechanism underlying acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). This histological transformation lacks effective treatments. We comprehensively discussed the treatments of transformed small cell lung cancer (T-SCLC) and analyzed the transcriptomic profile of EGFR\n                      <jats:sub>m<\/jats:sub>\n                      LUAD and paired T-SCLC, aiming to understand the immune landscape of this T-SCLC subtype.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Patients with pathologically confirmed lung adenocarcinoma (LUAD) at baseline who subsequently developed T-SCLC confirmed by re-biopsy after antitumor therapy resistance were included. For genomic and transcriptomic profiling, paired pre- and post-transformation specimens from EGFR-mutant patients were subjected to next-generation sequencing and RNA sequencing. Additionally, we integrated gene expression data for primary SCLC (P-SCLC) from the GEO database to compare the transformed and primary SCLC types.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      A total of 32 patients with pathologically confirmed LUAD at baseline who subsequently developed T-SCLC confirmed by re-biopsy after antitumor therapy resistance were included in this study. Among them, the median progression-free survival (mPFS) and overall survival (mOS) of T-SCLC with first-line immunotherapy plus chemotherapy were 5.1 and 21.0 months, respectively. Analysis of post-transformation treatments received after T-SCLC diagnosis revealed that patients exposed to immunotherapy had longer mOS than those who were immunotherapy-na\u00efve (21.0\u00a0m vs. 10.0\u00a0m,\n                      <jats:italic>P<\/jats:italic>\n                      \u2009=\u20090.03). Our data revealed that paired T-SCLC exhibited an immune-suppressive microenvironment compared with EGFR\n                      <jats:sub>m<\/jats:sub>\n                      LUAD, which included the downregulation of multiple immune regulatory pathways, reduced immune cell infiltration, decreased scores of immune-related signatures and downregulation expression of immune checkpoint-related genes. Additionally, we found that T-SCLC exhibited a more immunologically active microenvironment than P-SCLC, as evidenced by higher scores of immune-related signatures, including MHC signature, T cell-inflamed GEP signature and IFN-gamma signature.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      The immune landscape of T-SCLC is more immunosuppressed than EGFR\n                      <jats:sub>m<\/jats:sub>\n                      LUAD, yet more immunologically active than that of P-SCLC. This immune profile provides a rationale for integrating immunotherapy with chemotherapy in T-SCLC.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12967-026-08853-0","type":"journal-article","created":{"date-parts":[[2026,8,28]],"date-time":"2026-08-28T15:44:09Z","timestamp":1787931849000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Transcriptomic profiling of lineage transformation and actionable therapy opportunities in EGFR-mutant non-small cell lung cancer evolving to small cell lung cancer"],"prefix":"10.1186","volume":"24","author":[{"given":"Hui","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meichen","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodie","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjie","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingping","family":"Yun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7158-3878","authenticated-orcid":false,"given":"Likun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,28]]},"reference":[{"issue":"8","key":"8853_CR1","doi-asserted-by":"publisher","first-page":"2240","DOI":"10.1158\/1078-0432.Ccr-12-2246","volume":"15","author":"HA Yu","year":"2013","unstructured":"Yu HA, Arcila ME, Rekhtman N, et al. Analysis of tumor specimens at the time of acquired resistance to EGFR-TKI therapy in 155 patients with EGFR-mutant lung cancers. Clin Cancer Res Apr. 2013;15(8):2240\u20137. https:\/\/doi.org\/10.1158\/1078-0432.Ccr-12-2246.","journal-title":"Clin Cancer Res Apr"},{"issue":"75","key":"8853_CR2","doi-asserted-by":"publisher","first-page":"75ra26","DOI":"10.1126\/scitranslmed.3002003","volume":"23","author":"LV Sequist","year":"2011","unstructured":"Sequist LV, Waltman BA, Dias-Santagata D, et al. Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors. Sci Transl Med Mar. 2011;23(75):75ra26. https:\/\/doi.org\/10.1126\/scitranslmed.3002003.","journal-title":"Sci Transl Med Mar"},{"issue":"4","key":"8853_CR3","doi-asserted-by":"publisher","first-page":"e165","DOI":"10.1016\/s1470-2045(14)71180-5","volume":"16","author":"MG Oser","year":"2015","unstructured":"Oser MG, Niederst MJ, Sequist LV, Engelman JA. Transformation from non-small-cell lung cancer to small-cell lung cancer: molecular drivers and cells of origin. Lancet Oncol Apr. 2015;16(4):e165\u201372. https:\/\/doi.org\/10.1016\/s1470-2045(14)71180-5.","journal-title":"Lancet Oncol Apr"},{"issue":"7563","key":"8853_CR4","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1038\/nature14664","volume":"6","author":"J George","year":"2015","unstructured":"George J, Lim JS, Jang SJ, et al. Comprehensive genomic profiles of small cell lung cancer. Nat Aug. 2015;6(7563):47\u201353. https:\/\/doi.org\/10.1038\/nature14664.","journal-title":"Nat Aug"},{"issue":"26","key":"8853_CR5","doi-asserted-by":"publisher","first-page":"3065","DOI":"10.1200\/jco.2016.71.9096","volume":"10","author":"JK Lee","year":"2017","unstructured":"Lee JK, Lee J, Kim S, et al. Clonal History and Genetic Predictors of Transformation Into Small-Cell Carcinomas From Lung Adenocarcinomas. J Clin Oncol Sep. 2017;10(26):3065\u201374. https:\/\/doi.org\/10.1200\/jco.2016.71.9096.","journal-title":"J Clin Oncol Sep"},{"key":"8853_CR6","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1016\/j.lungcan.2021.03.006","volume":"155","author":"W Wang","year":"2021","unstructured":"Wang W, Xu C, Chen H, et al. Genomic alterations and clinical outcomes in patients with lung adenocarcinoma with transformation to small cell lung cancer after treatment with EGFR tyrosine kinase inhibitors: A multicenter retrospective study. Lung Cancer May. 2021;155:20\u20137. https:\/\/doi.org\/10.1016\/j.lungcan.2021.03.006.","journal-title":"Lung Cancer May"},{"issue":"10","key":"8853_CR7","doi-asserted-by":"publisher","first-page":"1265","DOI":"10.1097\/JTO.0b013e3182a407fa","volume":"8","author":"E Norkowski","year":"2013","unstructured":"Norkowski E, Ghigna MR, Lacroix L, et al. Small-cell carcinoma in the setting of pulmonary adenocarcinoma: new insights in the era of molecular pathology. J Thorac Oncol Oct. 2013;8(10):1265\u201371. https:\/\/doi.org\/10.1097\/JTO.0b013e3182a407fa.","journal-title":"J Thorac Oncol Oct"},{"issue":"1","key":"8853_CR8","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1186\/s12964-023-01260-8","volume":"17","author":"X Ding","year":"2024","unstructured":"Ding X, Shi MX, Liu D, et al. Transformation to small cell lung cancer is irrespective of EGFR and accelerated by SMAD4-mediated ASCL1 transcription independently of RB1 in non-small cell lung cancer. Cell Commun Signal Jan. 2024;17(1):45. https:\/\/doi.org\/10.1186\/s12964-023-01260-8.","journal-title":"Cell Commun Signal Jan"},{"key":"8853_CR9","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1016\/j.lungcan.2019.09.025","volume":"138","author":"J Bar","year":"2019","unstructured":"Bar J, Ofek E, Barshack I, et al. Transformation to small cell lung cancer as a mechanism of resistance to immunotherapy in non-small cell lung cancer. Lung Cancer Dec. 2019;138:109\u201315. https:\/\/doi.org\/10.1016\/j.lungcan.2019.09.025.","journal-title":"Lung Cancer Dec"},{"issue":"4","key":"8853_CR10","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1016\/j.jncc.2021.11.001","volume":"1","author":"J Zhong","year":"2021","unstructured":"Zhong J, Li X, Wang Z, et al. Evolution and genotypic characteristics of small cell lung cancer transformation in non-small cell lung carcinomas. J Natl Cancer Cent Dec. 2021;1(4):153\u201362. https:\/\/doi.org\/10.1016\/j.jncc.2021.11.001.","journal-title":"J Natl Cancer Cent Dec"},{"issue":"12","key":"8853_CR11","doi-asserted-by":"publisher","first-page":"3028","DOI":"10.1158\/2159-8290.Cd-20-1863","volume":"1","author":"A Quintanal-Villalonga","year":"2021","unstructured":"Quintanal-Villalonga A, Taniguchi H, Zhan YA, et al. Multiomic Analysis of Lung Tumors Defines Pathways Activated in Neuroendocrine Transformation. Cancer Discov Dec. 2021;1(12):3028\u201347. https:\/\/doi.org\/10.1158\/2159-8290.Cd-20-1863.","journal-title":"Cancer Discov Dec"},{"issue":"4","key":"8853_CR12","doi-asserted-by":"publisher","first-page":"278","DOI":"10.1200\/jco.18.01585","volume":"1","author":"N Marcoux","year":"2019","unstructured":"Marcoux N, Gettinger SN, O\u2019Kane G, et al. EGFR-Mutant Adenocarcinomas That Transform to Small-Cell Lung Cancer and Other Neuroendocrine Carcinomas: Clinical Outcomes. J Clin Oncol Feb. 2019;1(4):278\u201385. https:\/\/doi.org\/10.1200\/jco.18.01585.","journal-title":"J Clin Oncol Feb"},{"key":"8853_CR13","doi-asserted-by":"publisher","first-page":"6377","DOI":"10.1038\/ncomms7377","volume":"11","author":"MJ Niederst","year":"2015","unstructured":"Niederst MJ, Sequist LV, Poirier JT, et al. RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small-cell lung cancer. Nat Commun Mar. 2015;11:6:6377. https:\/\/doi.org\/10.1038\/ncomms7377.","journal-title":"Nat Commun Mar"},{"issue":"1","key":"8853_CR14","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1186\/s40364-025-00789-9","volume":"28","author":"H Sun","year":"2025","unstructured":"Sun H, Zhang CY, Zhang XH, et al. Transcriptomic analysis of transformed small-cell lung cancer from EGFR-mutated lung adenocarcinoma reveals distinct subgroups and precision therapy opportunities. Biomark Res May. 2025;28(1):79. https:\/\/doi.org\/10.1186\/s40364-025-00789-9.","journal-title":"Biomark Res May"},{"issue":"20","key":"8853_CR15","doi-asserted-by":"publisher","first-page":"4729","DOI":"10.1158\/1078-0432.Ccr-24-0160","volume":"15","author":"S Oh","year":"2024","unstructured":"Oh S, Koh J, Kim TM, et al. Transcriptomic Heterogeneity of EGFR-Mutant Non-Small Cell Lung Cancer Evolution Toward Small-Cell Lung Cancer. Clin Cancer Res Oct. 2024;15(20):4729\u201342. https:\/\/doi.org\/10.1158\/1078-0432.Ccr-24-0160.","journal-title":"Clin Cancer Res Oct"},{"issue":"12","key":"8853_CR16","doi-asserted-by":"publisher","first-page":"2002","DOI":"10.1016\/j.jtho.2021.07.018","volume":"16","author":"BH Herzog","year":"2021","unstructured":"Herzog BH, Devarakonda S, Govindan R. Overcoming Chemotherapy Resistance in SCLC. J Thorac Oncol Dec. 2021;16(12):2002\u201315. https:\/\/doi.org\/10.1016\/j.jtho.2021.07.018.","journal-title":"J Thorac Oncol Dec"},{"key":"8853_CR17","doi-asserted-by":"publisher","unstructured":"Zhang C, Zhang S, Yao Y, et al. MA12.08 Chemotherapy plus EGFR TKIs or Bevacizumab versus chemotherapy alone in SCLC-transformed EGFR-mutant lung adenocarcinoma. J Thorac Oncol. 2021;16(3):S178\u20139. https:\/\/doi.org\/10.1016\/j.jtho.2021.01.259.","DOI":"10.1016\/j.jtho.2021.01.259"},{"issue":"19","key":"8853_CR18","doi-asserted-by":"publisher","first-page":"2585","DOI":"10.1111\/1759-7714.14144","volume":"12","author":"S Wang","year":"2021","unstructured":"Wang S, Xie T, Hao X, et al. Comprehensive analysis of treatment modes and clinical outcomes of small cell lung cancer transformed from epidermal growth factor receptor mutant lung adenocarcinoma. Thorac Cancer Oct. 2021;12(19):2585\u201393. https:\/\/doi.org\/10.1111\/1759-7714.14144.","journal-title":"Thorac Cancer Oct"},{"issue":"6","key":"8853_CR19","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1200\/jco.20.01055","volume":"20","author":"SV Liu","year":"2021","unstructured":"Liu SV, Reck M, Mansfield AS, et al. Updated Overall Survival and PD-L1 Subgroup Analysis of Patients With Extensive-Stage Small-Cell Lung Cancer Treated With Atezolizumab, Carboplatin, and Etoposide (IMpower133). J Clin Oncol Feb. 2021;20(6):619\u201330. https:\/\/doi.org\/10.1200\/jco.20.01055.","journal-title":"J Clin Oncol Feb"},{"issue":"10212","key":"8853_CR20","doi-asserted-by":"publisher","first-page":"1929","DOI":"10.1016\/s0140-6736(19)32222-6","volume":"23","author":"L Paz-Ares","year":"2019","unstructured":"Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet Nov. 2019;23(10212):1929\u201339. https:\/\/doi.org\/10.1016\/s0140-6736(19)32222-6.","journal-title":"Lancet Nov"},{"issue":"8","key":"8853_CR21","doi-asserted-by":"publisher","first-page":"990","DOI":"10.1002\/cac2.70032","volume":"45","author":"Y Cheng","year":"2025","unstructured":"Cheng Y, Zhang S, Han L, et al. First-line serplulimab plus chemotherapy in extensive-stage small-cell lung cancer: Updated results and biomarker analysis from the ASTRUM-005 randomized clinical trial. Cancer Commun (Lond) Aug. 2025;45(8):990\u20131009. https:\/\/doi.org\/10.1002\/cac2.70032.","journal-title":"Cancer Commun (Lond) Aug"},{"key":"8853_CR22","doi-asserted-by":"publisher","first-page":"68","DOI":"10.1016\/j.lungcan.2022.11.016","volume":"175","author":"CY Zhang","year":"2023","unstructured":"Zhang CY, Sun H, Su JW, et al. A potential treatment option for transformed small-cell lung cancer on PD-L1 inhibitor-based combination therapy improved survival. Lung Cancer Jan. 2023;175:68\u201378. https:\/\/doi.org\/10.1016\/j.lungcan.2022.11.016.","journal-title":"Lung Cancer Jan"},{"issue":"23","key":"8853_CR23","doi-asserted-by":"publisher","first-page":"e2317790121","DOI":"10.1073\/pnas.2317790121","volume":"4","author":"C Yang","year":"2024","unstructured":"Yang C, Ma S, Zhang J, et al. EHMT2-mediated transcriptional reprogramming drives neuroendocrine transformation in non-small cell lung cancer. Proc Natl Acad Sci U S Jun. 2024;4(23):e2317790121. https:\/\/doi.org\/10.1073\/pnas.2317790121.","journal-title":"Proc Natl Acad Sci U S Jun"},{"issue":"14","key":"8853_CR24","doi-asserted-by":"publisher","first-page":"3916","DOI":"10.1158\/0008-5472.Can-20-4048","volume":"15","author":"K Ishioka","year":"2021","unstructured":"Ishioka K, Yasuda H, Hamamoto J, et al. Upregulation of FGF9 in Lung Adenocarcinoma Transdifferentiation to Small Cell Lung Cancer. Cancer Res Jul. 2021;15(14):3916\u201329. https:\/\/doi.org\/10.1158\/0008-5472.Can-20-4048.","journal-title":"Cancer Res Jul"},{"issue":"5","key":"8853_CR25","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1089\/omi.2011.0118","volume":"16","author":"G Yu","year":"2012","unstructured":"Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. Omics May. 2012;16(5):284\u20137. https:\/\/doi.org\/10.1089\/omi.2011.0118.","journal-title":"Omics May"},{"key":"8853_CR26","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-14-7","author":"S H\u00e4nzelmann","year":"2013","unstructured":"H\u00e4nzelmann S, Castelo R, Guinney. GSVA: gene set variation analysis for microarray and RNA-seq data. J. BMC Bioinf Jan. 2013;16:14:7. https:\/\/doi.org\/10.1186\/1471-2105-14-7."},{"key":"8853_CR27","doi-asserted-by":"publisher","unstructured":"Charoentong P, Finotello F, Angelova M, et al. Pan-cancer immunogenomic analyses reveal genotype-immunophenotype relationships and predictors of response to checkpoint blockade. Cell Rep. 2017;18(1):248\u2013262. https:\/\/doi.org\/10.1016\/j.celrep.2016.12.019.","DOI":"10.1016\/j.celrep.2016.12.019"},{"issue":"1","key":"8853_CR28","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1186\/s13073-019-0638-6","volume":"24","author":"F Finotello","year":"2019","unstructured":"Finotello F, Mayer C, Plattner C, et al. Molecular and pharmacological modulators of the tumor immune contexture revealed by deconvolution of RNA-seq data. Genome Med May. 2019;24(1):34. https:\/\/doi.org\/10.1186\/s13073-019-0638-6.","journal-title":"Genome Med May"},{"issue":"8","key":"8853_CR29","doi-asserted-by":"publisher","first-page":"2930","DOI":"10.1172\/jci91190","volume":"1","author":"M Ayers","year":"2017","unstructured":"Ayers M, Lunceford J, Nebozhyn M, et al. IFN-\u03b3-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Invest Aug. 2017;1(8):2930\u201340. https:\/\/doi.org\/10.1172\/jci91190.","journal-title":"J Clin Invest Aug"},{"key":"8853_CR30","doi-asserted-by":"publisher","unstructured":"Davoli T, Uno H, Wooten EC, Elledge SJ. Tumor aneuploidy correlates with markers of immune evasion and with reduced response to immunotherapy. Sci Jan. 2017;20(6322). https:\/\/doi.org\/10.1126\/science.aaf8399.","DOI":"10.1126\/science.aaf8399"},{"issue":"1\u20132","key":"8853_CR31","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1016\/j.cell.2014.12.033","volume":"15","author":"MS Rooney","year":"2015","unstructured":"Rooney MS, Shukla SA, Wu CJ, Getz G, Hacohen N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell Jan. 2015;15(1\u20132):48\u201361. https:\/\/doi.org\/10.1016\/j.cell.2014.12.033.","journal-title":"Cell Jan"},{"issue":"2","key":"8853_CR32","doi-asserted-by":"publisher","first-page":"188589","DOI":"10.1016\/j.bbcan.2021.188589","volume":"1876","author":"K Duraivelan","year":"2021","unstructured":"Duraivelan K, Samanta D. Emerging roles of the nectin family of cell adhesion molecules in tumour-associated pathways. Biochim Biophys Acta Rev Cancer Dec. 2021;1876(2):188589. https:\/\/doi.org\/10.1016\/j.bbcan.2021.188589.","journal-title":"Biochim Biophys Acta Rev Cancer Dec"},{"issue":"8","key":"8853_CR33","doi-asserted-by":"publisher","first-page":"1186","DOI":"10.1016\/j.jtho.2024.03.019","volume":"19","author":"LY Hu","year":"2024","unstructured":"Hu LY, Zhuang WT, Chen MJ, et al. EGFR Oncogenic Mutations in NSCLC Impair Macrophage Phagocytosis and Mediate Innate Immune Evasion Through Up-Regulation of CD47. J Thorac Oncol Aug. 2024;19(8):1186\u2013200. https:\/\/doi.org\/10.1016\/j.jtho.2024.03.019.","journal-title":"J Thorac Oncol Aug"},{"issue":"10","key":"8853_CR34","doi-asserted-by":"publisher","first-page":"842","DOI":"10.1016\/j.neo.2017.07.007","volume":"19","author":"B Oronsky","year":"2017","unstructured":"Oronsky B, Reid TR, Oronsky A, Carter CA. What\u2019s New in SCLC? A Review. Neoplasia Oct. 2017;19(10):842\u20137. https:\/\/doi.org\/10.1016\/j.neo.2017.07.007.","journal-title":"Neoplasia Oct"},{"issue":"6","key":"8853_CR35","doi-asserted-by":"publisher","first-page":"620","DOI":"10.3322\/caac.21785","volume":"73","author":"Z Megyesfalvi","year":"2023","unstructured":"Megyesfalvi Z, Gay CM, Popper H, et al. Clinical insights into small cell lung cancer: Tumor heterogeneity, diagnosis, therapy, and future directions. Cancer J Clin. 2023;73(6):620\u201352. https:\/\/doi.org\/10.3322\/caac.21785.","journal-title":"Cancer J Clin"},{"key":"8853_CR36","doi-asserted-by":"publisher","unstructured":"Lally BE, Urbanic JJ, Blackstock AW, Miller AA, Perry MC. Small cell lung cancer: have we made any progress over the last 25 years? Oncologist. 2007;12(9):1096\u2013104. https:\/\/doi.org\/10.1634\/theoncologist.12-9-1096","DOI":"10.1634\/theoncologist.12-9-1096"},{"issue":"5","key":"8853_CR37","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1038\/s41568-019-0133-9","volume":"19","author":"CM Rudin","year":"2019","unstructured":"Rudin CM, Poirier JT, Byers LA, et al. Molecular subtypes of small cell lung cancer: a synthesis of human and mouse model data. Nat Rev Cancer May. 2019;19(5):289\u201397. https:\/\/doi.org\/10.1038\/s41568-019-0133-9.","journal-title":"Nat Rev Cancer May"},{"issue":"3","key":"8853_CR38","doi-asserted-by":"publisher","first-page":"346","DOI":"10.1016\/j.ccell.2020.12.014","volume":"8","author":"CM Gay","year":"2021","unstructured":"Gay CM, Stewart CA, Park EM, et al. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. Cancer Cell Mar. 2021;8(3):346\u2013e3607. https:\/\/doi.org\/10.1016\/j.ccell.2020.12.014.","journal-title":"Cancer Cell Mar"},{"key":"8853_CR39","doi-asserted-by":"publisher","first-page":"115065","DOI":"10.1016\/j.ejca.2024.115065","volume":"213","author":"FC Saalfeld","year":"2024","unstructured":"Saalfeld FC, M\u00f6ller J, Christopoulos P, et al. Small cell transformation in EGFR-mutated non-small cell lung cancer: DLL3 expression and efficacy of immune checkpoint inhibitors or tyrosine kinase inhibitors combined with chemotherapy. Eur J Cancer Dec. 2024;213:115065. https:\/\/doi.org\/10.1016\/j.ejca.2024.115065.","journal-title":"Eur J Cancer Dec"},{"issue":"7","key":"8853_CR40","doi-asserted-by":"publisher","first-page":"105326","DOI":"10.1016\/j.esmoop.2025.105326","volume":"10","author":"C Catania","year":"2025","unstructured":"Catania C, Liu SV, Garassino M, et al. Correlation between treatments and outcomes of patients with EGFR-mutated non-small-cell lung cancer that transitioned into small-cell lung cancer: an international retrospective study. ESMO Open Jul. 2025;10(7):105326. https:\/\/doi.org\/10.1016\/j.esmoop.2025.105326.","journal-title":"ESMO Open Jul"},{"issue":"3","key":"8853_CR41","doi-asserted-by":"publisher","first-page":"452","DOI":"10.21037\/tlcr-21-665","volume":"11","author":"L Yu","year":"2022","unstructured":"Yu L, Bazhenova L, Gold K, et al. Clinicopathologic and molecular characteristics of EGFR-mutant lung adenocarcinomas that transform to small cell lung cancer after TKI therapy. Transl Lung Cancer Res Mar. 2022;11(3):452\u201361. https:\/\/doi.org\/10.21037\/tlcr-21-665.","journal-title":"Transl Lung Cancer Res Mar"},{"issue":"3","key":"8853_CR42","doi-asserted-by":"publisher","first-page":"639","DOI":"10.1007\/s00428-025-04054-0","volume":"487","author":"A Nambirajan","year":"2025","unstructured":"Nambirajan A, Rathor A, Baskarane H, et al. Baseline retinoblastoma transcriptional corepressor 1 (Rb1) functional inactivation is a pre-requisite but not sufficient for small-cell histological transformation in epidermal growth factor receptor (EGFR) mutant lung adenocarcinomas post-tyrosine kinase inhibitor therapy. Virchows Arch Sep. 2025;487(3):639\u201348. https:\/\/doi.org\/10.1007\/s00428-025-04054-0.","journal-title":"Virchows Arch Sep"},{"issue":"4","key":"8853_CR43","doi-asserted-by":"publisher","first-page":"927","DOI":"10.1002\/ijc.29835","volume":"138","author":"L Meder","year":"2016","unstructured":"Meder L, K\u00f6nig K, Ozreti\u0107 L, et al. NOTCH, ASCL1, p53 and RB alterations define an alternative pathway driving neuroendocrine and small cell lung carcinomas. Int J Cancer Feb 15. 2016;138(4):927\u201338. https:\/\/doi.org\/10.1002\/ijc.29835.","journal-title":"Int J Cancer Feb 15"},{"issue":"2","key":"8853_CR44","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1056\/NEJMoa1713137","volume":"11","author":"JC Soria","year":"2018","unstructured":"Soria JC, Ohe Y, Vansteenkiste J, et al. Osimertinib in Untreated EGFR-Mutated Advanced Non-Small-Cell Lung Cancer. N Engl J Med Jan. 2018;11(2):113\u201325. https:\/\/doi.org\/10.1056\/NEJMoa1713137.","journal-title":"N Engl J Med Jan"},{"key":"8853_CR45","doi-asserted-by":"publisher","unstructured":"Hong S, Gao F, Fu S, et al. Concomitant genetic alterations with response to treatment and epidermal growth factor receptor tyrosine kinase inhibitors in patients with EGFR-mutant advanced non-small cell lung cancer. JAMA Oncol. 2018;4(5):739\u2013742. https:\/\/doi.org\/10.1001\/jamaoncol.2018.0049.","DOI":"10.1001\/jamaoncol.2018.0049"},{"issue":"6","key":"8853_CR46","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1038\/s41577-019-0127-6","volume":"19","author":"DG DeNardo","year":"2019","unstructured":"DeNardo DG, Ruffell B. Macrophages as regulators of tumour immunity and immunotherapy. Nat Rev Immunol Jun. 2019;19(6):369\u201382. https:\/\/doi.org\/10.1038\/s41577-019-0127-6.","journal-title":"Nat Rev Immunol Jun"}],"container-title":["Journal of Translational Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12967-026-08853-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12967-026-08853-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12967-026-08853-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T12:48:37Z","timestamp":1790254117000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s12967-026-08853-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,28]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["8853"],"URL":"https:\/\/doi.org\/10.1186\/s12967-026-08853-0","relation":{"references":[{"id-type":"doi","id":"10.1186\/1471-2105-14-7IF:","asserted-by":"subject"}]},"ISSN":["1479-5876"],"issn-type":[{"value":"1479-5876","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,28]]},"assertion":[{"value":"13 March 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"13 August 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"28 August 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 September 2026","order":6,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Update","order":7,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Article updated to correct the equal contribution statement.","order":8,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"This study involves human participants and was approved by the Institutional Ethics Committee of SYSUCC (No. SL-B2026-217-01).","order":1,"name":"Ethics","label":"Ethical approval","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"In accordance with its retrospective design and in compliance with the ethical principles of the Declaration of Helsinki (as revised in 2013), the requirement for written informed consent was waived.","order":2,"name":"Ethics","label":"Consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare that they have no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"1123"}}