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

   

Authors:	Chakraborty, S.; Coleman, C.; Manoj, P.; Demircioglu, D.; Shah, N.; de Stanchina, E.; Rudin, C. M.; Hasson, D.; Sen, T.
Article Title:	De novo and histologically transformed small-cell lung cancer is sensitive to lurbinectedin treatment through the modulation of EMT and NOTCH signaling pathways
Abstract:	Purpose: 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 (OS) of those who benefit from it remains very low (∼9.3 months). This finding highlights the need to develop improved mechanistic insight and predictive biomarkers of response. Experimental Design: We used human and patient-derived xenograft (PDX)-derived SCLC cell lines to evaluate the effect of lurbinectedin in vitro. We also demonstrate the antitumor effect of lurbinectedin in multiple de novo and transformed SCLC PDX models. Changes in gene and protein expression pre- and postlurbinectedin treatment was assessed by RNA sequencing and Western blot analysis. Results: Lurbinectedin markedly reduced cell viability in the 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 antitumor response in multiple models of EGFR-mutant lung adenocarcinoma with histologic transformation to SCLC. Transcriptomic analysis identified induction of apoptosis, repression of epithelial-mesenchymal transition, modulation of PI3K/AKT, 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. © 2023 American Association for Cancer Research.
Keywords:	signal transduction; genetics; lung neoplasms; pathology; phosphatidylinositol 3 kinase; lung tumor; small cell lung cancer; small cell lung carcinoma; phosphatidylinositol 3-kinases; humans; human; lurbinectedin
Journal Title:	Clinical Cancer Research
Volume:	29
Issue:	17
ISSN:	1078-0432
Publisher:	American Association for Cancer Research
Date Published:	2023-09-01
Start Page:	3526
End Page:	3540
Language:	English
DOI:	10.1158/1078-0432.Ccr-23-0471
PUBMED:	37382635
PROVIDER:	scopus
PMCID:	PMC10901109
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85169502487&doi=10.1158%2f1078-0432.CCR-23-0471&partnerID=40&md5=805f86d102c3796f7587f68de1c72d1a
Notes:	Article -- Source: Scopus

https://synapse.mskcc.org/synapse/works/has_related_data_chk/209842