Emerging advances in defining the molecular and therapeutic landscape of small-cell lung cancer

Small-cell lung cancer (SCLC) has traditionally been considered a recalcitrant cancer with a dismal prognosis, with only modest advances in therapeutic strategies over the past several decades. Comprehensive genomic assessments of SCLC have revealed that most of these tumours harbour deletions of the tumour-suppressor genes TP53 and RB1 but, in contrast to non-small-cell lung cancer, have failed to identify targetable alterations. The expression status of four transcription factors with key roles in SCLC pathogenesis defines distinct molecular subtypes of the disease, potentially enabling specific therapeutic approaches. Overexpression and amplification of MYC paralogues also affect the biology and therapeutic vulnerabilities of SCLC. Several other attractive targets have emerged in the past few years, including inhibitors of DNA-damage-response pathways, epigenetic modifiers, antibody-drug conjugates and chimeric antigen receptor T cells. However, the rapid development of therapeutic resistance and lack of biomarkers for effective selection of patients with SCLC are ongoing challenges. Emerging single-cell RNA sequencing data are providing insights into the plasticity and intratumoural and intertumoural heterogeneity of SCLC that might be associated with therapeutic resistance. In this Review, we provide a comprehensive overview of the latest advances in genomic and transcriptomic characterization of SCLC with a particular focus on opportunities for translation into new therapeutic approaches to improve patient outcomes. Traditionally, patients with small-cell lung cancer (SCLC), a malignancy with a dismal prognosis, have had limited treatment options. Over the past few years, advances in the molecular characterization of SCLC have revealed novel therapeutic targets. The authors of this Review summarize these findings and discuss emerging opportunities and challenges for their translation into new treatment approaches. Continuing to improve the biological understanding and therapeutic strategies for early-stage small-cell lung cancer (SCLC) remains a critical need to improve the overall prognosis of SCLC.Immune checkpoint inhibitors improve the overall survival in a minority of patients with extensive-stage SCLC (ES-SCLC). Repression of MHC I-dependent antigen-presentation machinery and low infiltration of cytotoxic T lymphocytes remain major challenges in improving outcome in a majority of patients with ES-SCLC.The major transcriptional subtypes of SCLC have distinct biology and therapeutic vulnerabilities. However, application of SCLC subtypes as clinically actionable biomarkers continues to be a challenge.Intratumoural heterogeneity and plasticity after treatment highlight the complexity of SCLC and present potential hurdles in treatment strategies for relapsed SCLC. Improvement in single-cell analysis methods, liquid biopsy platforms and rapid research autopsy programmes will potentially facilitate the understanding of SCLC biology, capturing the intratumoural heterogeneity and plasticity in treatment-resistant SCLC.Novel cell surface targets (such as DLL3, SEZ6, TROP2 and B7-H3) and MHC-independent immunotherapy strategies are paving the path for promising clinical trials.Results of the phase III ADRIATIC trial in limited-stage SCLC and accelerated FDA approval of tarlatamab for the treatment of ES-SCLC demonstrate significant advances in the treatment of SCLC. Future work will focus on understanding treatment resistance and potential combinatorial strategies to improve the therapeutic landscape in SCLC.