ISL1 Emerges as a Potential Predictive Biomarker for Efficacy of Lurbinectedin in Relapsed SCLC
Key Clinical Takeaways:
- Key Outcomes: Proteomic profiling identified ISL1 as a novel predictive biomarker for lurbinectedin response in SCLC; ISL1 expression correlated with durable clinical benefit, enhanced DNA damage, and functional tumor dependency, while SLFN11 was not predictive.
- Design/Population: Translational analysis of 16 patients with relapsed SCLC treated with lurbinectedin, including molecular profiling of pretreatment tumors and functional validation in SCLC cell lines.
- Clinical Relevance: ISL1 defines a previously unrecognized SCLC subtype with heightened sensitivity to lurbinectedin, supporting biomarker-driven patient selection and informing prospective clinical trials.
Proteomic analysis in a translational study identified Insulin gene enhancer protein (ISL1) as a novel predictive biomarker in small cell lung cancer (SCLC), defining a distinct subtype with enhanced sensitivity to lurbinectedin and supporting biomarker-driven patient selection in future trials.
Small cell lung cancer remains one of the most treatment-refractory malignancies, characterized by rapid development of chemoresistance, early metastatic spread, and poor overall survival. Although lurbinectedin—a DNA minor groove-binding alkylating agent—has demonstrated durable responses in a subset of patients with relapsed disease, reliable biomarkers to predict benefit have been lacking.
In a recent translational study, investigators evaluated molecular predictors of lurbinectedin response in 16 patients with relapsed SCLC treated with the agent. Patients were stratified by treatment durability, including 8 “durable responders” who received at least 8 cycles of therapy (mean, 14.75 cycles; median progression-free survival, 9.8 months). Pretreatment tumor specimens were analyzed using immunohistochemistry (IHC) and tandem mass tag–labeled proteomic profiling, with top candidates subsequently validated in SCLC cell line models.
Contrary to prior expectations, SLFN11—a biomarker associated with response to other DNA-damaging agents—did not predict lurbinectedin efficacy (P = 0.40). Instead, proteomic analysis identified enrichment of a primitive neuroendocrine transcriptional program involving ISL1, SOX5, SIX1, and SIX4. Among these, ISL1 expression showed a significant correlation with clinical response to lurbinectedin (r = 0.65; P = 0.035). IHC analyses further demonstrated reduced ISL1 expression following treatment, suggesting a direct pharmacodynamic effect.
Functional studies revealed that lurbinectedin preferentially induced DNA damage in ISL1-high SCLC cells without driving neuroendocrine subtype switching. RNA sequencing confirmed downregulation of ISL1 and associated neuroendocrine regulators, including ASCL1, SOX5, and SIX1, alongside upregulation of the stress-response gene ATF3. Importantly, ISL1-high SCLC cells were shown to be dependent on ISL1 for survival, and ISL1 knockdown reduced sensitivity to lurbinectedin. Regulatory pathway analysis indicated that L-MYC positively regulates ISL1, which in turn maintains expression of ASCL1 and SOX5.
This study represents the first comprehensive effort to identify predictive biomarkers for lurbinectedin in SCLC and defines ISL1 as both a biomarker of sensitivity and a functional dependency. The findings suggest that ISL1 marks a previously unrecognized SCLC subtype with enhanced vulnerability to lurbinectedin. Prospective clinical studies evaluating ISL1-guided patient selection for lurbinectedin therapy are planned and may help refine treatment strategies in this challenging disease.
Source:
Shields M, Minton K G, Ozakinci H, et al. ISL1: A novel neuroendocrine subtype in small cell lung cancer predicts durable response to lurbinectedin. Mol Cancer Ther. Published online January 26, 2026. https://aacrjournals.org/mct/article-abstract/doi/10.1158/1535-7163.MCT-25-0663/771954/ISL1-A-Novel-Neuroendocrine-Subtype-in-Small-Cell
