Abstract
Transformed small-cell lung cancer (tSCLC) from EGFR-mutant adenocarcinoma is a rare and aggressive form of lung cancer that can occur when the tumor develops resistance to EGFR targeted therapy and the cancer cells acquire additional genomic alterations that cause them to transform into SCLC. Treatment for tSCLC has not been established yet, and chemotherapy regimens for de novo SCLC are mostly recommended. However, these treatments showed disappointing outcome, and novel anti-cancer agents and immunological approaches are currently being developed. The patient-derived cell line is a critical tool for pre-clinical and translational research, but cell line models for tSCLC are not publicly available from cell banks. The aim of this study was to establish and characterize a novel cell line for tSCLC. Using a lymph-node biopsy tissue from a 58-year-old female patient, whose tumor was EGFR-mutant lung adenocarcinoma progressed on afatinib, we successfully established a cell line, named BMC-PDC-019. The tumor sample and cell line showed a typical expression of SCLC markers, such as CD56 and synaptophysin. The population doubling-time of BMC-PDC-019 cells was 48 h. We examined a range of proliferation-inhibiting effects of anti-cancer drugs currently used for de novo SCLC, using BMC-PDC-019 cells. We concluded that BMC-PDC-019 would be a useful tool for pre-clinical and translational research.
Similar content being viewed by others
References
Sabari JK, Lok BH, Laird JH, Poirier JT, Rudin CM. Unravelling the biology of SCLC: implications for therapy. Nat Rev Clin Oncol. 2017;14:549–61.
Passaro A, Leighl N, Blackhall F, Popat S, Kerr K, Ahn MJ, et al. ESMO expert consensus statements on the management of EGFR mutant non-small-cell lung cancer. Ann Oncol. 2022;33:466–87.
Camidge DR, Pao W, Sequist LV. Acquired resistance to TKIs in solid tumours: learning from lung cancer. Nat Rev Clin Oncol. 2014;11:473–81.
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. 2015;16:e165-172.
Marcoux N, Gettinger SN, O’Kane G, Arbour KC, Neal JW, Husain H, et al. EGFR-mutant adenocarcinomas that transform to small-cell lung cancer and other neuroendocrine carcinomas: clinical outcomes. J Clin Oncol. 2019;37:278–85.
Yin X, Li Y, Wang H, Jia T, Wang E, Luo Y, et al. Small cell lung cancer transformation: from pathogenesis to treatment. Semin Cancer Biol. 2022;86:595–606.
Liang X, Lin A, Wang Q, Zhang J, Luo P. Cell plasticity in patients with NSCLC: the controversial origins of transformed SCLC. Biomed Pharmacother. 2022;149: 112909.
Xie T, Li Y, Ying J, Cai W, Li J, Lee KY, et al. Whole exome sequencing (WES) analysis of transformed small cell lung cancer (SCLC) from lung adenocarcinoma (LUAD). Transl Lung Cancer Res. 2020;9:2428–39.
Lee JK, Lee J, Kim S, Kim S, Youk J, Park S, et al. Clonal history and genetic predictors of transformation into small-cell carcinomas from lung adenocarcinomas. J Clin Oncol. 2017;35:3065–74.
Park CK, Oh IJ, Kim YC. Is transformed small cell lung cancer (SCLC) different from de novo SCLC? Transl Cancer Res. 2019;8:346–9.
Tokaca N, Wotherspoon A, Nicholson AG, Fotiadis N, Thompson L, Popat S. Lack of response to nivolumab in a patient with EGFR-mutant non-small cell lung cancer adenocarcinoma sub-type transformed to small cell lung cancer. Lung Cancer. 2017;111:65–8.
Xu J, Xu L, Wang B, Kong W, Chen Y, Yu Z. Outcomes in patients with lung adenocarcinoma with transformation to small cell lung cancer after EGFR tyrosine kinase inhibitors resistance: a systematic review and pooled analysis. Front Oncol. 2021;11: 766148.
Tlemsani C, Pongor L, Elloumi F, Girard L, Huffman KE, Roper N, et al. SCLC-cellminer: a resource for small cell lung cancer cell line genomics and pharmacology based on genomic signatures. Cell Rep. 2020;33: 108296.
Oostdik K, French J, Yet D, Smalling B, Nolde C, Vallone PM, et al. Developmental validation of the PowerPlex(R) 18D System, a rapid STR multiplex for analysis of reference samples. Forensic Sci Int Genet. 2013;7:129–35.
Robin T, Capes-Davis A, Bairoch A. CLASTR: the cellosaurus STR similarity search tool -A precious help for cell line authentication. Int J Cancer. 2020;146:1299–306.
Kim JS, Lee SC, Min HY, Park KH, Hyun SY, Kwon SJ, et al. Activation of insulin-like growth factor receptor signaling mediates resistance to histone deacetylase inhibitors. Cancer Lett. 2015;361:197–206.
Hobeika C, Rached G, Eid R, Haddad F, Chucri S, Kourie HR, et al. ALK-rearranged adenocarcinoma transformed to small-cell lung cancer: a new entity with specific prognosis and treatment? Per Med. 2018;15:111–5.
Caumont C, Veillon R, Gros A, Laharanne E, Begueret H, Merlio JP. Neuroendocrine phenotype as an acquired resistance mechanism in ALK-rearranged lung adenocarcinoma. Lung Cancer. 2016;92:15–8.
Cha YJ, Cho BC, Kim HR, Lee HJ, Shim HS. A case of ALK-rearranged adenocarcinoma with small cell carcinoma-like transformation and resistance to crizotinib. J Thorac Oncol. 2016;11:e55–8.
Ou SI, Lee TK, Young L, Fernandez-Rocha MY, Pavlick D, Schrock AB, et al. Dual occurrence of ALK G1202R solvent front mutation and small cell lung cancer transformation as resistance mechanisms to second generation ALK inhibitors without prior exposure to crizotinib. Pitfall of solely relying on liquid re-biopsy? Lung Cancer. 2017;106:110–4.
Gazeu A, Aubert M, Pissaloux D, Lantuejoul S, Perol M, Ikhlef N, et al. Small-cell lung cancer transformation as a mechanism of resistance to pralsetinib in RET-rearranged lung adenocarcinoma: a case report. Clin Lung Cancer. 2023;24:72–5.
Lin JJ, Langenbucher A, Gupta P, Yoda S, Fetter IJ, Rooney M, et al. Small cell transformation of ROS1 fusion-positive lung cancer resistant to ROS1 inhibition. NPJ Precis Oncol. 2020;4:21.
Imakita T, Fujita K, Kanai O, Okamura M, Hashimoto M, Nakatani K, et al. Small cell transformation of non-small cell lung cancer under immunotherapy: case series and literature review. Thorac Cancer. 2021;12:3062–7.
Sehgal K, Varkaris A, Viray H, VanderLaan PA, Rangachari D, Costa DB. Small cell transformation of non-small cell lung cancer on immune checkpoint inhibitors: uncommon or under-recognized? J Immunother Cancer. 2020;8:e000697.
Wang W, Xu C, Chen H, Jia J, Wang L, Feng 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. 2021;155:20–7.
Hwang S, Hong TH, Park S, Jung HA, Sun JM, Ahn JS, et al. Molecular subtypes of small cell lung cancer transformed from adenocarcinoma after EGFR tyrosine kinase inhibitor treatment. Transl Lung Cancer Res. 2021;10:4209–20.
Piper-Vallillo AJ, Sequist LV, Piotrowska Z. Emerging treatment paradigms for EGFR-mutant lung cancers progressing on osimertinib: a review. J Clin Oncol. 2020. https://doi.org/10.1200/JCO.19.03123.
Meador CB, Lovly CM. A tale of two histologies: dissecting the biology of lineage transformation in lung cancer. Cancer Discov. 2021;11:2962–4.
Petty WJ, Paz-Ares L. Emerging strategies for the treatment of small cell lung cancer: a review. JAMA Oncol. 2022. https://doi.org/10.1001/jamaoncol.2022.5631.
Herzog BH, Devarakonda S, Govindan R. Overcoming Chemotherapy Resistance in SCLC. J Thorac Oncol. 2021;16:2002–15.
Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. Signatures of mutational processes in human cancer. Nature. 2013;500:415–21.
Horn L, Mansfield AS, Szczesna A, Havel L, Krzakowski M, Hochmair MJ, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379:2220–9.
Liu SV, Reck M, Mansfield AS, Mok T, Scherpereel A, Reinmuth N, 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. 2021;39:619–30.
Zhang CY, Sun H, Su JW, Chen YQ, Zhang SL, Zheng MY, et al. A potential treatment option for transformed small-cell lung cancer on PD-L1 inhibitor-based combination therapy improved survival. Lung Cancer. 2023;175:68–78.
Funding
This research was financially supported by the Boramae Medical Center (Grant No. 04-2022-0039).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
No potential conflict of interest relevant to this article was reported.
Ethical approval
The ethical committee of Boramae Medical Center approved the use of clinical materials for this study with the approved number (26–2015-65).
Informed consent
Consent for publication was provided by the patient.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Kim, M.Y., Jung, S.Y., Hong, S. et al. Establishment and characterization of BMC-PDC-019: a novel patient-derived cell line of EGFR-mutant pulmonary adenocarcinoma transformed into small-cell lung cancer. Human Cell 36, 2179–2186 (2023). https://doi.org/10.1007/s13577-023-00980-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13577-023-00980-w