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. Lurbinectedin, a DNA minor groove alkylating agent, provides durable efficacy in a minority. Predictive biomarkers for lurbinectedin are needed. Patients with relapsed SCLC who received lurbinectedin (n=16) were classified by cycles received, including eight durable responders defined as ≥8 cycles (average, 14.75 cycles; median PFS, 9.8 months). Pretreatment specimens were analyzed by immunohistochemistry (IHC) for SLFN11 and tandem mass tag (TMT)-labeled expression proteomics. Top candidates were confirmed by IHC and functionally validated in SCLC cell lines. SLFN11 failed to predict lurbinectedin response (P = 0.40). Proteomics highlighted a primitive neuroendocrine pathway (ISL1, SOX5, SIX1, SIX4). ISL1 expression significantly correlated with lurbinectedin response (r = 0.65, P = 0.0351). IHC confirmed lurbinectedin reduced ISL1 post-treatment. Lurbinectedin preferentially induced DNA damage in ISL1 "high" SCLC (P <0.0001) without causing neuroendocrine subtype switching. RNA sequencing showed downregulation of ISL1, RBMS3, ASCL1, SOX5, SIX1, and upregulation of ATF3. ISL1 "high" SCLC demonstrated cellular dependency on ISL1; ISL1 knockdown reduced lurbinectedin sensitivity. L-MYC positively regulated ISL1, while ISL1 positively regulated ASCL1 and SOX5. This is the first comprehensive investigation of predictive biomarkers for lurbinectedin. Proteomics identified ISL1 as defining a novel SCLC subtype with enhanced lurbinectedin sensitivity. ISL1 serves as both a predictive biomarker and functional dependency, as evidenced by essentiality for cell survival and loss following treatment. Prospective studies using ISL1 as a predictive biomarker for lurbinectedin are planned.