Promoters of ASCL1‐ and NEUROD1‐dependent genes are specific targets of lurbinectedin in SCLC cells

Abstract

SCLC is poorly responding to current therapies and the need to find new therapeutic strategies is posing a major issue to impact disease progression. This study propose how a DNA binder named here lurbinectedin, might use the transcription addiction of SCLC cells as an opportunity for new therapeutical endeavor through targeting and blocking transcriptional program of undruggable key transcription factors involved in disease progression and poor survival. -. ASCL1 and NEUROD1 target their E-box cognate sequence and control the expression of a large number of genes in SCLC. -. lurbinectedin, a marine alkaloid, is able to target the central G rich triplets found in CpG islands mainly located downstream from the transcription start site of most of genes. -. Binding of lurbinectedin abolishes the expression of ASCL1 and NEUROD1 target genes, such as INSM1, MYC, MYB and BCL2. -. Blocking ASCL1 and NEUROD1 transcriptional program drives SCLC cell lines towards programmed cell death and profoundly impact tumorigenesis.