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

Abstract

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.

Application of Small Cell Lung Cancer Molecular Subtyping Markers to Small Cell Neuroendocrine Carcinoma of the Cervix

“…23,24 Recent studies have reported on the potential effects of targeted therapies, such as aurora kinase inhibitors and lurbinectedin, in NEUROD1-dominant SCLC. 23,25 In contrast, NEUROD1 has not been studied in CSCNEC so far. Considering that NEUROD1-dominant CSCNEC shows similar clinical behavior to SCLC, the application of targeted therapies for NEUROD1-dominant SCLC could be considered in CSCNEC with further accumulation of supporting evidence.…”

“…In SCLC, the NEUROD1-dominant subtype was shown to be associated with extensive disease and poor prognosis by promoting tumor cell migration through tyrosine kinase tropomyosin-related kinase B and neural cell adhesion molecule, which are pro-metastatic signaling molecules 23,24 . Recent studies have reported on the potential effects of targeted therapies, such as aurora kinase inhibitors and lurbinectedin, in NEUROD1-dominant SCLC 23,25 . In contrast, NEUROD1 has not been studied in CSCNEC so far.…”

NEUROD1 predicts better prognosis in pancreatic cancer revealed by a TILs-based prognostic signature

“…In addition to regulating the tumor progression, NEUROD1 could be also a drug target in cancer therapy. In small-cell lung cancer, NEUROD1-dependent genes are specific targets of lurbinectedin ( Costanzo et al, 2022 ). Moreover, NEUROD1 could be used as a marker for efficacy monitoring as well.…”

A matter of delicate balance: Loss and gain of Cockayne syndrome proteins in premature aging and cancer

“…It is well documented that CS proteins participate in RNA pol I and II mediated basal and activated transcription ( Balajee et al, 1997 ; Selby and Sancar, 1997 ; Bradsher et al, 2002 ; Yuan et al, 2007 ; Brooks et al, 2008 ; Koch et al, 2014 ; Lanzafame et al, 2021 ). In this context, it is worth noting the role of CSB in the transcriptional activation of some key genes, as neuroD1 ( Ciaffardini et al, 2014 ), whose tight regulation is well known to be required to avoid the trigger of dysregulatory mechanisms for initiating and promoting oncogenic activities ( Costanzo et al, 2022 ). For this reason, it might be of interest investigating if CSB overexpression is causative for the abnormal regulation of these key genes and, consequently, for the induction of the hyperactivation cascades aimed to direct cell fate towards abnormal survival and proliferation.…”