119P - De novo and histologically transformed small-cell lung cancer is sensitive to lurbinectedin treatment through the modulation of EMT and NOTCH signaling pathways

Background

Small-cell lung cancer (SCLC) is a high-grade neuroendocrine tumor with a 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. 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.

Methods

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 were assessed by RNA sequencing and western blot analysis.

Results

Lurbinectedin markedly reduced cell viability in a 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, and NOTCH signaling associated with lurbinectedin response in de novo and transformed SCLC models.

Conclusions

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.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The author.

Funding

Has not received any funding.

Disclosure

The author has declared no conflicts of interest.