ISL1: A Novel Neuroendocrine Subtype in Small Cell Lung Cancer Predicts Durable Response to Lurbinectedin

Small cell lung cancer (SCLC) is a recalcitrant thoracic malignancy known for acquired chemoresistance, early metastatic spread, and poor overall survival. Treatment with lurbinectedin, a DNA minor groove alkylating agent, provides durable efficacy in a subset of patients. In this study, we aim to identify and validate predictive biomarkers to lurbinectedin in small cell lung cancer patients. Within the ISL1 “high” lines, 1,105 genes were uniquely downregulated following lurbinectedin, including ISL1, RBMS3, PARD3B, SIX1, SOX2-OT, AURKA, and ASCL1. Downregulation of select MYC paralogs was additionally observed in the ISL1 “high” lines. Over 1,100 genes were additionally identified to be uniquely upregulated in the ISL1 “high” lines, including ATF3, BEST1, and DDIT3. ISL1 “low” lines showed significantly fewer unique expression changes following lurbinectedin (35 downregulated, 25 upregulated). Regardless of ISL1 status, 83 genes were globally downregulated, including LSAMP and MACROD2, while only 14 genes were globally upregulated following lurbinectedin, including TONSL, CDT1, and CHTF18.