Small cell lung cancer (SCLC) is currently treated as a homogenous cancer, resulting in dismal outcomes. Gay and colleagues characterized four molecularly distinct SCLC subtypes based on transcription factor expression (ASCL1, NEUROD1, and POU2F3). The fourth novel subtype was defined by the presence of a mesenchymal and inflammatory phenotype and absence of transcription factor expression (SCLC-I). SCLC-I patients had the greatest benefit from immunotherapy, while the three other subtypes had improved responses preclinically to PARP, Aurora kinase, or BCL2 inhibitors, respectively. Subtype plasticity was observed during platinum resistance with subtype transdifferentiation to the SCLC-I subtype.

Expert Commentary: This study suggests that transcription factor expression subtyping of SCLC may enable precision therapy.

Gay CM, Stewart CA, Park EM, Diao L, Groves SM, Heeke S, et al. Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities. Cancer Cell; Published online January 5,...

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