Subtype-specific dependencies and therapeutic opportunities in small cell lung cancer

Small cell lung cancer (SCLC), accounting for ~15% of lung cancers, is an aggressive and lethal tumor type. It is characterized by rapid proliferation, early metastasis, and poor prognosis. Current therapies, including platinum-based chemotherapy and recently introduced immune checkpoint inhibitors, provide modest survival benefits due to frequent relapse and therapeutic resistance. At the molecular level, SCLC is marked by near-universal loss of the tumor suppressors genes TP53 and RB1, and exhibits marked heterogeneity driven by several key master transcription factors. These factors define distinct molecular subtypes with unique gene expression programs and therapeutic vulnerabilities, enabling cell plasticity and subtype switching in response to treatment pressures. A thorough understanding of these subtype-specific dependencies and the epigenetic mechanisms regulating transcription is critical for developing effective and durable therapies. This review focuses on these aspects and evaluates the potential of epigenetic-targeted strategies in the treatment of SCLC.