Lurbinectedin is an effective therapeutic target for de novo and transformed small cell lung cancer and modulates EMT and NOTCH signaling pathways.

Small cell lung cancer (SCLC) is a high-grade neuroendocrine tumor with a dismal prognosis and limited treatment options. Lurbinectedin, approved as a second-line treatment for metastatic SCLC, showed only a partial response in clinical trials highlighting the need to develop improved mechanistic insight and predictive biomarkers of response. In this study, we determine the preclinical efficacy of lurbinectedin in a comprehensive panel of SCLC cell lines and patient-derived xenografts of SCLC. Furthermore, we demonstrate that lurbinectedin, either as a single agent or in combination with osimertinib, causes remarkable anti-tumor response in multiple models of SCLC transformation. Transcriptomic analysis identified induction of apoptosis, repression EMT and modulation of PI3K/AKT, NOTCH signalling pathway being associated with lurbinectedin response in de novo and transformed SCLC models. We provide a mechanistic insight of lurbinectedin response in SCLC and is the first demonstration that lurbinectedin is a potential therapeutic target after SCLC transformation. Overall design: RNA.seq analysis data of small cell lung cancer of 3 patient derived xenograft models of de-novo small cell lung cancer (LX110, LX33 and LX1322) in lurbinectedin treated and vehicle treated group. Data also include RNA seq analysis of 2 patient derived xenograft models of transformed SCLC , LX1042 and LX831b comparing vehicle, only osimertinib, only lurbinectedin and lurbinectedin+osimertinib combination treatment groups.