Comprehensive Genomic Profiling of Small-Cell Lung Cancer Reveals Frequent Potentially Targetable Alterations

Small-cell lung carcinoma (SCLC) remains one of the most aggressive lung cancers and continues to pose a major challenge for precision oncology. Despite its morphological uniformity, SCLC exhibits marked molecular heterogeneity with recurrent, potentially targetable genomic alterations. Comprehensive profiling is often hindered by limited tissue availability and the need for rapid therapeutic intervention. We performed genomic profiling of 55 primary and metastatic SCLC samples using a 324-gene hybrid-capture next-generation sequencing panel. Consistent with prior reports, nearly all tumors exhibited biallelic <i>TP53</i> and <i>RB1</i> inactivation. Recurrent alterations involved the PI3K/Akt/mTOR pathway (62%), chromatin regulators (42%), and NOTCH signaling genes (15%). <i>PTEN</i> mutations were enriched in brain metastases. Frequent copy-number gains affected <i>SOX2</i>, <i>NKX2-1</i>, MYC-family genes, and <i>CCNE1</i>. Two novel recurrent amplifications of potential clinical significance were identified: <i>TYRO3</i> (33%) and <i>SDHA</i> (13%). <i>TYRO3</i>, a TAM family receptor tyrosine kinase, and <i>SDHA</i>, a mitochondrial enzyme involved in succinate metabolism, may contribute to tumor progression and represent emerging therapeutic vulnerabilities. These findings underscore the genomic diversity of SCLC and highlight the potential utility of broad next-generation sequencing in uncovering new molecular targets for precision therapy.