title: MYCL is a target of a BET bromodomain inhibitor, JQ1, on growth suppression efficacy in small cell lung cancer cells.
abstract: We aimed to elucidate the effect of JQ1, a BET inhibitor, on small cell lung cancers (SCLCs) with MYCL amplification and/or expression. Fourteen SCLC cell lines, including four with MYCL amplification, were examined for the effects of JQ1 on protein and gene expression by Western blot and mRNA microarray analyses. The sensitivity of SCLC cells to JQ1 was assessed by cell growth and apoptosis assays. MYCL was expressed in all the 14 cell lines, whereas MYC/MYCN expression was restricted mostly to cell lines with gene amplification. ASCL1, a transcription factor shown to play a role in SCLC, was also expressed in 11/14 cell lines. All SCLC cell lines were sensitive to JQ1 with GI50 values ≤1.23 μM, with six of them showing GI50 values <0.1 μM. Expression of MYCL as well as MYCN, ASCL1 and other driver oncogenes including CDK6 was reduced by JQ1 treatment, in particular in the cell lines with high expression of the respective genes; however, no association was observed between the sensitivity to JQ1 and the levels of MYCL, MYCN and ASCL1 expression. In contrast, levels of CDK6 expression and its reduction rates by JQ1 were associated with JQ1 sensitivity. Therefore, we concluded that CDK6 is a novel target of JQ1 and predictive marker for JQ1 sensitivity in SCLC cells.
authors.affiliation: Genomics and Epigenomics of Cancer Prediction Program, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Campus Can Ruti, Badalona, Barcelona, Spain.
authors.forename: Fuyumi
authors.initials: F
authors.lastname: Kato
authors.affiliation: Genomics and Epigenomics of Cancer Prediction Program, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Campus Can Ruti, Badalona, Barcelona, Spain.
authors.forename: Francesco Paolo
authors.initials: FP
authors.lastname: Fiorentino
authors.affiliation: Genomics and Epigenomics of Cancer Prediction Program, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Campus Can Ruti, Badalona, Barcelona, Spain.
authors.forename: Andreu
authors.initials: A
authors.lastname: Alibés
authors.affiliation: Genomics and Epigenomics of Cancer Prediction Program, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Campus Can Ruti, Badalona, Barcelona, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Perucho
authors.affiliation: Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Montse
authors.initials: M
authors.lastname: Sánchez-Céspedes
authors.affiliation: Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kohno
authors.affiliation: Genomics and Epigenomics of Cancer Prediction Program, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Campus Can Ruti, Badalona, Barcelona, Spain.|Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Yokota
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001381:Azepines / Q000494:pharmacology*; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D005784:Gene Amplification; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D055752:Small Cell Lung Carcinoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D059467:Transcriptome; D014230:Triazoles / Q000494:pharmacology*
chemical_list: C561695:(+)-JQ1 compound; D000970:Antineoplastic Agents; D001381:Azepines; C000596782:MYCL protein, human; D016271:Proto-Oncogene Proteins c-myc; D014230:Triazoles; D051361:Cyclin-Dependent Kinase 6
keywords: CDK6; JQ1; MYCL; cell cycle arrest; small cell lung cancer