Integrating molecular subtypes, genomics and functional dependencies to identify context-specific therapeutic...

Small cell lung cancer is one of the most aggressive malignancies, characterized by rapid tumor growth, early metastatic spread and extremely poor survival. Although most patients initially respond to platinum-based chemotherapy, relapse is almost inevitable and treatment options at recurrence remain limited. The recent introduction of immune checkpoint inhibitors has provided only modest clinical benefit, largely due to the fact that these tumors are immunologically cold. These limitations highlight the urgent need to better understand the molecular features of small cell lung cancer in order to identify more effective therapeutic strategies. In this review, we summarize current knowledge of the molecular landscape of small cell lung cancer, with particular emphasis on transcriptome-based classifications that have identified four major molecular subtypes defined by distinct transcriptional regulators and gene expression programs. We discuss how these classifications have improved the biological understanding of the disease and stimulated efforts to develop subtype-specific therapeutic strategies. At the same time, we highlight important limitations of this framework, including the remarkable transcriptional plasticity of tumor cells, which allows dynamic transitions between subtypes and may contribute to therapeutic resistance. To address these challenges, we examine additional molecular features that may represent more stable vulnerabilities, including recurrent genomic alterations, such as the widespread loss of tumor suppressor genes or oncogene amplifications through extrachromosomal DNA. We also discuss emerging approaches aimed at identifying novel context-specific cancer dependencies, including genome-scale functional screens in vitro and in vivo and genetic restraint analyses. Finally, we consider the growing potential of liquid biopsy strategies, which exploit the high level of circulating tumor DNA in patients with this disease to detect clinically relevant genomic alterations and monitor tumor evolution. Overall, this review highlights both the opportunities and challenges associated with molecular stratification in small cell lung cancer. The integration of transcriptional classifications with genomic and functional approaches may help identify more robust therapeutic vulnerabilities and guide the development of more effective treatments for this highly aggressive disease.