Data from De novo and histologically transformed small cell lung cancer is sensitive to lurbinectedin treatment through the modulation of EMT and NOTCH signaling pathways.

AbstractPurpose: Small cell lung cancer (SCLC) is a high-grade neuroendocrine tumor with dismal prognosis and limited treatment options. Lurbinectedin, conditionally approved as a second-line treatment for metastatic SCLC, drives clinical responses in about 35% of patients and the overall survival of those who benefit from it remains very low (~9.3 months). This highlights the need to develop improved mechanistic insight and predictive biomarkers of response. Experimental Design: We used human and PDX-derived SCLC cell lines to evaluate the effect of lurbinectedin in vitro. We also demonstrate the anti-tumor effect of lurbinectedin in multiple de novo and transformed SCLC PDX models. Changes in gene and protein expression pre- and post-lurbinectedin treatment was assessed by RNA sequencing and western blot analysis. Results: Lurbinectedin markedly reduced cell viability in majority of SCLC models with the best response on POU2F3-driven SCLC cells. We further demonstrate that lurbinectedin, either as a single agent or in combination with osimertinib, causes an appreciable anti-tumor response in multiple models of EGFR-mutant lung adenocarcinoma with histologic transformation to SCLC. Transcriptomic analysis identified induction of apoptosis, repression of EMT, modulation of PI3K/AKT, NOTCH signaling associated with lurbinectedin response in de novo and transformed SCLC models. Conclusion: Our study provides a mechanistic insight into lurbinectedin response in SCLC and the first demonstration that lurbinectedin is a potential therapeutic target after SCLC transformation.