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

Carl M Gay
C Allison Stewart
Elizabeth M Park
Lixia Diao
Sarah M Groves
Simon Heeke
Barzin Y Nabet
Junya Fujimoto
Luisa M Solis
Wei Lu
Yuanxin Xi
Robert J Cardnell
Qi Wang
Giulia Fabbri
Kasey R Cargill
Natalie I Vokes
Kavya Ramkumar
Bingnan Zhang
Carminia M Della Corte
Paul Robson, The Jackson Laboratory
Stephen G Swisher
Jack A Roth
Bonnie S Glisson
David S Shames
Ignacio I Wistuba
Jing Wang
Vito Quaranta
John Minna
John V Heymach
Lauren Averett Byers


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.