The tissue distribution and prognostic relevance of subtype-specific proteins (ASCL1, NEUROD1, POU2F3, YAP1) present an evolving area of research in small-cell lung cancer (SCLC). The expression of subtype-specific transcription factors and P53 and RB1 proteins were measured by immunohistochemistry (IHC) in 386 surgically resected SCLC samples. Correlations between subtype-specific proteins and in vitro efficacy of various therapeutic agents were investigated by proteomics and cell viability assays in 26 human SCLC cell lines. Besides SCLC-A (ASCL1-dominant), SCLC-AN (combined ASCL1/NEUROD1), SCLC-N (NEUROD1-dominant), and SCLC-P (POU2F3-dominant), IHC and cluster analyses identified a quadruple-negative SCLC subtype (SCLC-QN). No unique YAP1-subtype was found. The highest overall survival rates were associated with non-neuroendocrine subtypes (SCLC-P and SCLC-QN) and the lowest with neuroendocrine subtypes (SCLC-A, SCLC-N, SCLC-AN). In univariate analyses, high ASCL1 expression was associated with poor prognosis and high POU2F3 expression with good prognosis. Notably, high ASCL1 expression influenced survival outcomes independently of other variables in a multivariate model. High POU2F3 and YAP1 protein abundances correlated with sensitivity and resistance to standard-of-care chemotherapeutics, respectively. Specific correlation patterns were also found between the efficacy of targeted agents and subtype-specific protein abundances. In conclusion, we investigated the clinicopathological relevance of SCLC molecular subtypes in a large cohort of surgically resected specimens. Differential IHC expression of ASCL1, NEUROD1, and POU2F3 defines SCLC subtypes. No YAP1-subtype can be distinguished by IHC. High POU2F3 expression is associated with improved survival in a univariate analysis, whereas elevated ASCL1 expression is an independent negative prognosticator. Proteomic and cell viability assays of human SCLC cell lines revealed distinct vulnerability profiles defined by transcription regulators. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

1st Department of Pathology and Experimental Cancer Research Semmelweis University Budapest Hungary

Department of Biomedical Engineering Lund University Lund Sweden

Department of Pathology Medical University of Vienna Vienna Austria

Department of Pathology University Hospital Ostrava and Faculty of Medicine University of Ostrava Ostrava Czech Republic

Department of Physics of Complex Systems Eotvos Lorand University Budapest Hungary

Department of Surgery University Hospital Ostrava and Faculty of Medicine University of Ostrava Ostrava Czech Republic

Department of Thoracic Surgery Comprehensive Cancer Center Medical University of Vienna Vienna Austria

Department of Thoracic Surgery Klinik Floridsdorf Vienna Austria

Department of Thoracic Surgery Semmelweis University and National Institute of Oncology Budapest Hungary

Diagnostic and Research Institute of Pathology Medical University of Graz Graz Austria

Division of Medical Oncology University of Colorado Anschutz Medical Campus Aurora CO USA

Division of Oncology Department of Internal Medicine and Oncology Semmelweis University Budapest Hungary

Institute of Clinical and Molecular Pathology Medical Faculty Palacky University Olomouc Olomouc Czech Republic

MTA SE NAP Brain Metastasis Research Group Hungarian Academy of Sciences Budapest Hungary

National Koranyi Institute of Pulmonology Budapest Hungary

Tisch Cancer Institute Center for Thoracic Oncology Mount Sinai Health System New York NY USA

Torokbalint County Institute of Pulmonology Torokbalint Hungary

University Clinic for Respiratory and Allergic Diseases Golnik Golnik Slovenia

Zobrazit více v PubMed

Gazdar AF, Bunn PA, Minna JD. Small‐cell lung cancer: what we know, what we need to know and the path forward. Nat Rev Cancer 2017; 17: 725–737. PubMed

Kahnert K, Kauffmann‐Guerrero D, Huber RM. SCLC‐state of the art and what does the future have in store? Clin Lung Cancer 2016; 17: 325–333. PubMed

Schwendenwein A, Megyesfalvi Z, Barany N, PubMed PMC

Rudin CM, Poirier JT, Byers LA, PubMed PMC

Lee YC, Chang YL, Luh SP, PubMed

Drapkin BJ, Rudin CM. Advances in small‐cell lung cancer (SCLC) translational research. Cold Spring Harb Perspect Med 2021; 11: a038240. PubMed PMC

Karachaliou N, Sosa AE, Rosell R. Unraveling the genomic complexity of small cell lung cancer. Transl Lung Cancer Res 2016; 5: 363–366. PubMed PMC

George J, Lim JS, Jang SJ, PubMed PMC

Gazdar AF, Carney DN, Nau MM, PubMed

Mollaoglu G, Guthrie MR, Böhm S, PubMed PMC

Borromeo MD, Savage TK, Kollipara RK, PubMed PMC

Baine MK, Hsieh MS, Lai WV, PubMed PMC

Huang YH, Klingbeil O, He XY, PubMed PMC

McColl K, Wildey G, Sakre N, PubMed PMC

Gay CM, Stewart CA, Park EM, PubMed PMC

Ireland AS, Micinski AM, Kastner DW, PubMed PMC

Simpson KL, Stoney R, Frese KK, PubMed

Rudin CM, Brambilla E, Faivre‐Finn C, PubMed PMC

Nicholson SA, Beasley MB, Brambilla E, PubMed

Hoda MA, Klikovits T, Klepetko W. Controversies in oncology: surgery for small cell lung cancer? It's time to rethink the case. ESMO Open 2018; 3: e000366. PubMed PMC

Sato Y, Okamoto I, Kameyama H, PubMed PMC

Qu S, Fetsch P, Thomas A, PubMed PMC

Kaiser U, Schilli M, Haag U, PubMed

Ben‐Ezra JM, Kornstein MJ, Grimes MM, PubMed PMC

Gandhi JS, Alnoor F, Sadiq Q, PubMed

Travis WD. Update on small cell carcinoma and its differentiation from squamous cell carcinoma and other non‐small cell carcinomas. Mod Pathol 2012; 25: S18–S30. PubMed

Pelosi G, Rindi G, Travis WD, PubMed

Thunnissen E, Borczuk AC, Flieder DB, PubMed

Qi J, Zhang J, Liu N, PubMed PMC

Lai WCV, Egger JV, Rizvi H,

Wallace WA, Dorward DA, Salter DM. Immunohistochemistry for small‐cell carcinoma: a potential diagnostic pitfall. Histopathology 2019; 74: 792–794. PubMed

Carney DN, Gazdar AF, Bepler G, PubMed

Gibney GT, Weiner LM, Atkins MB. Predictive biomarkers for checkpoint inhibitor‐based immunotherapy. Lancet Oncol 2016; 17: e542–e551. PubMed PMC

Bai R, Lv Z, Xu D, PubMed PMC

Welter S, Aigner C, Roesel C. The role of surgery in high grade neuroendocrine tumours of the lung. J Thorac Dis 2017; 9: S1474–S1483. PubMed PMC

Asamura H, Kameya T, Matsuno Y, PubMed

Furuta M, Sakakibara‐Konishi J, Kikuchi H, PubMed PMC

Kosari F, Ida CM, Aubry MC, PubMed PMC

Dora D, Rivard C, Yu H, PubMed PMC

Gazdar AF. Molecular Phenotypes of SCLC. In International Association for the Study of Lung Cancer ‐ 19th World Conference on Lung Cancer, September 23–26, 2018 Abstract MS3204, 2018. JTO: Toronto, 2018.

Saunders LR, Bankovich AJ, Anderson WC, PubMed PMC

Zhang W, Girard L, Zhang YA, PubMed PMC

Picard Leblanc G, Blais N, Tehfe M,

Wang XD, Hu R, Ding Q, PubMed PMC

Fujii K, Miyata Y, Takahashi I, PubMed

Byers LA, Wang J, Nilsson MB, PubMed PMC

Ito T, Matsubara D, Tanaka I, PubMed PMC

Thng DKH, Toh TB, Chow EKH. Capitalizing on synthetic lethality of MYC to treat cancer in the digital age. Trends Pharmacol Sci 2021; 42: 166–182. PubMed

Grillo F, Bruzzone M, Pigozzi S, PubMed

Kokkat TJ, Patel MS, McGarvey D, PubMed PMC

Kalemkerian GP, Loo BW, Akerley W, PubMed

Battifora H. The multitumor (sausage) tissue block: novel method for immunohistochemical antibody testing. Lab Invest 1986; 55: 244–248. PubMed

Kuras M, Woldmar N, Kim Y, PubMed

Comparative profiling of surgically resected primary tumors and their lymph node metastases in small-cell lung cancer