Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities

• Published in: Cancer cell Vol. 39; no. 3; pp. 346 - 360.e7
• Main Authors: Gay, Carl M., Stewart, C. Allison, Park, Elizabeth M., Diao, Lixia, Groves, Sarah M., Heeke, Simon, Nabet, Barzin Y., Fujimoto, Junya, Solis, Luisa M., Lu, Wei, Xi, Yuanxin, Cardnell, Robert J., Wang, Qi, Fabbri, Giulia, Cargill, Kasey R., Vokes, Natalie I., Ramkumar, Kavya, Zhang, Bingnan, Della Corte, Carminia M., Robson, Paul, Swisher, Stephen G., Roth, Jack A., Glisson, Bonnie S., Shames, David S., Wistuba, Ignacio I., Wang, Jing, Quaranta, Vito, Minna, John, Heymach, John V., Byers, Lauren Averett
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.03.2021
• Subjects: Animals; ASCL1; Cell Line, Tumor; Cisplatin - pharmacology; EMT; Female; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - immunology; Humans; Immunity - drug effects; Immunity - immunology; intratumoral heterogeneity; Lung Neoplasms - drug therapy; Lung Neoplasms - immunology; Mice; Mice, Nude; NEUROD1; neuroendocrine; POU2F3; Prognosis; SCLC; Small Cell Lung Carcinoma - drug therapy; Small Cell Lung Carcinoma - immunology; Transcription Factors - immunology; NEUROD1; SCLC; neuroendocrine; intratumoral heterogeneity; ASCL1; POU2F3; EMT
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccell.2020.12.014

Despite molecular and clinical heterogeneity, small cell lung cancer (SCLC) is treated as a single entity with predictably poor results. Using tumor expression data and non-negative matrix factorization, we identify four SCLC subtypes defined largely by differential expression of transcription factors ASCL1, NEUROD1, and POU2F3 or low expression of all three transcription factor signatures accompanied by an Inflamed gene signature (SCLC-A, N, P, and I, respectively). SCLC-I experiences the greatest benefit from the addition of immunotherapy to chemotherapy, while the other subtypes each have distinct vulnerabilities, including to inhibitors of PARP, Aurora kinases, or BCL-2. Cisplatin treatment of SCLC-A patient-derived xenografts induces intratumoral shifts toward SCLC-I, supporting subtype switching as a mechanism of acquired platinum resistance. We propose that matching baseline tumor subtype to therapy, as well as manipulating subtype switching on therapy, may enhance depth and duration of response for SCLC patients. [Display omitted] •Differential expression of ASCL1, NEUROD1, and POU2F3 defines SCLC subtypes•An inflamed SCLC subtype (SCLC-I) has low expression of ASCL1, NEUROD1, and POU2F3•SCLC-I experiences greatest benefit from the addition of anti-PD-L1 to chemotherapy•Subtype switching accompanies acquired resistance to platinum chemotherapy Gay et al. provide a classification for four subtypes of small cell lung cancer, each with unique molecular features and therapeutic vulnerabilities. An inflamed, mesenchymal subtype predicts benefit with the addition of immunotherapy to chemotherapy. Intratumoral switching between chemosensitive and chemoresistant subtypes accompanies therapeutic resistance.