Abstract
<jats:p><div>Abstract<p>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 (<i>n</i> = 16) were classified by cycles received, including eight durable responders defined as ≥8 cycles (average, 14.75 cycles; median progression-free survival, 9.8 months). Pretreatment specimens were analyzed by immunohistochemistry (IHC) for Schlafen-11 (SLFN11) and tandem mass tag–labeled expression proteomics. Top candidates were confirmed by IHC and functionally validated in SCLC cell lines. SLFN11 failed to predict lurbinectedin response (<i>P</i> = 0.40). Proteomics highlighted a primitive neuroendocrine (NE) pathway [Islet-1 (ISL1), SOX5, SIX1, SIX4]. ISL1 expression significantly correlated with lurbinectedin response (<i>r</i> = 0.65; <i>P</i> = 0.0351). IHC confirmed that lurbinectedin reduced ISL1 after treatment. Lurbinectedin preferentially induced DNA damage in ISL1-“high” SCLC (<i>P</i> < 0.0001) without causing NE subtype switching. RNA sequencing showed downregulation of ISL1, RBMS3, ASCL1, SOX5, and SIX1 and upregulation of ATF3. ISL1-“high” SCLC demonstrated cellular dependency on ISL1; ISL1 knockdown reduced lurbinectedin sensitivity. L-MYC positively regulated ISL1, whereas 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 a functional dependency, as evidenced by its essentiality for cell survival and loss following treatment. Prospective studies using ISL1 as a predictive biomarker for lurbinectedin are planned.</p></div></jats:p>