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

EMBO Molecular Medicine

Juan Ignacio Díaz‐Hernandéz¹  Marta Martínez Diez¹  Javier Díez Pérez¹  Juan Fernando Martínez Leal¹  Gema Santamaría Nuñez¹  Eva Maria Garrido‐Martin¹  Tsai‐Kun Li²  Jean Marc Egly³  Carlos Mario Genes Robles³  Frédéric Coin³  Emmanuel Compe³  Federico Costanzo³  Romeo Ricci³ 

[1] Cell Biology Department, Research and Development Pharmamar SA Colmenar Viejo Spain;College of Medicine Center for Genomics and Precision Medicine National Taiwan University Taipei city Taiwan;Department of Functional Genomics and Cancer IGBMC, CNRS/INSERM/University of Strasbourg Equipe labellisée Ligue contre le Cancer Strasbourg France;

关键词: ASCL1/NEUROD1;    E‐boxes/CpG islands;    lurbinectedin;    transcription addiction;   

DOI  :  10.15252/emmm.202114841

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown