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

Small‐Cell Lung Cancer (SCLC) is an aggressive neuroendocrine malignancy with a poor prognosis. Here, we focus on the neuroendocrine SCLC subtypes, SCLC‐A and SCLC‐N, whose transcription addiction was driven by ASCL1 and NEUROD1 transcription factors which target E‐box motifs to activate up to 40% of total genes, the promoters of which are maintained in a steadily open chromatin environment according to ATAC and H3K27Ac signatures. This leverage is used by the marine agent lurbinectedin, which preferentially targets the CpG islands located downstream of the transcription start site, thus arresting elongating RNAPII and promoting its degradation. This abrogates the expression of ASCL1 and NEUROD1 and of their dependent genes, such as BCL2 , INSM1 , MYC , and AURKA , which are responsible for relevant SCLC tumorigenic properties such as inhibition of apoptosis and cell survival, as well as for a part of its neuroendocrine features. In summary, we show how the transcription addiction of these cells becomes their Achilles’s heel, and how this is effectively exploited by lurbinectedin as a novel SCLC therapeutic endeavor. Synopsis SCLCs poorly respond to current treatments, underlying the need for new therapeutic strategies. This study reports how the DNA binder lurbinectedin benefits from the SCLC cells transcription addiction to block the transcriptional program of key transcription factors involved in disease progression. 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, targets the central G rich triplets found in CpG islands mainly located downstream from the genes transcription start site. Lurbinectedin binding abolishes the expression of ASCL1 and NEUROD1 target genes, such as INSM1, MYC, MYB and BCL2. Blocking ASCL1 and NEUROD1 transcriptional program drives SCLC cells towards programmed cell death and deeply impacts tumorigenesis. Graphical Abstract SCLCs poorly respond to current treatments, underlying the need for new therapeutic strategies. This study reports how the DNA binder lurbinectedin benefits from the SCLC cells transcription addiction to block the transcriptional program of key transcription factors involved in disease progression.