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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., Competing Interests: Declaration of interests C.M.G. reports research funding from AstraZeneca. S.H. reports consulting/honoraria from Qiagen, Boehringer Ingelheim and travel funding from Roche. B.Y.Z. and D.S.S. are employees of Genentech, Inc. G.F. is an employee of AstraZeneca and has stock ownership in AstraZeneca. B.G. reports research funding from ISA Pharm, Cue Bio, Pfizer, and Medimmune. I.I.W. reports consulting/advisory roles for Medscape, MSD, Genentech/Roche, PlatformQ Health, Pfizer, Bayer, Bristol-Myers Squibb, AstraZeneca/Medimmune, HTG Molecular, Asuragen, Merck, GlaxoSmithKline, Guardant Health, Oncocyte, and MSD, research support from Genentech, Oncoplex, HTG Molecular, DepArray, Merck, Bristol-Myers Squibb, Medimmune, Adapative, Adaptimmune, EMD Serono, Pfizer, Takeda, Amgen, Karus, Johnson & Johnson, Bayer, Iovance, 4D, Novartis and Akoya. J.V.H. serves on advisory committees for AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Guardant Health, Kairos Venture Investments, BrightPath Biotherapeutics, Hengrui Therapeutics, Eli Lilly, Spectrum, EMD Serono, Roche, and Foundation One Medicine and has research support from AstraZeneca, Spectrum, and Checkmate Pharmaceuticals, as well as royalties/licensing fees from Spectrum and Bio-Tree Systems. L.A.B. serves on advisory committees for AstraZeneca, AbbVie, GenMab, BergenBio, Pharma Mar SA, Sierra Oncology, Merck, Bristol-Myers Squibb, Genentech, and Pfizer and has research support from AbbVie, AstraZeneca, GenMab, Sierra Oncology, Tolero Pharmaceuticals. C.M.G., L.A.B., and J.V.H. have pending patent applications for SCLC subtyping U.S. 62/895,322. Otherwise, there are no pertinent financial or non-financial conflicts of interest to report., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In this issue of Cancer Cell, Mohammad et al. describe LSD1, a histone demethylase, as a therapeutic target in SCLC with a unique epigenetic signature to predict drug sensitivity. Inhibition of LSD1 reduces cell proliferation and stem cell maintenance while promoting cell differentiation and reducing tumor growth in preclinical models., (Copyright © 2015 Elsevier Inc. All rights reserved.)