Targeting MYC in small cell lung cancer: Bridging molecular subtypes and therapeutic vulnerability

Small cell lung cancer (SCLC) is one of the most aggressive and rapidly progressing forms of lung cancer, characterized by its high proliferative rate and strong tendency to metastasize. Although SCLC initially responds well to platinum-based chemotherapy, resistance typically develops quickly, leaving few effective options and resulting in poor overall survival. Immunotherapies, including PD-1/PD-L1 inhibitors have been introduced in clinical settings and other drugs, such as antibody-drug conjugates, are being actively studied, but their efficacy has so far been limited. Despite a shared genetic foundation, most notably the near-universal loss of tumor suppressor genes TP53 and RB1, alongside frequent over-activation of the MYC family of oncogenes (MYC, MYCN, MYCL), SCLC exhibits remarkable diversity at the molecular level. Historically, classification of SCLC was based on the presence or absence of neuroendocrine features. However, recent advances have shifted the paradigm toward a transcription factor-driven framework that defines molecular subtypes. One of the key areas of current investigation is understanding the multifaceted role of oncogenic activation of MYC family members in SCLC biology. Given its prominent involvement in driving certain subtypes of the disease, it represents a critical axis of vulnerability that may be exploited for therapeutic use. By dissecting how MYC oncogenic activity varies across molecular subtypes, this review aims to highlight novel opportunities for targeted interventions that could improve clinical outcomes for specific patient populations. This review explores the underlying mechanisms that drive SCLC initiation and progression, focusing on tumor heterogeneity, immune landscape, and especially the role of oncogenic MYC in promoting metastasis and therapeutic resistance. We further explore how recent insights into these processes are shaping emerging treatment strategies, with an emphasis on targeting molecular vulnerabilities within distinct MYC-driven subtypes.