title: HEXIM1 as a Robust Pharmacodynamic Marker for Monitoring Target Engagement of BET Family Bromodomain Inhibitors in Tumors and Surrogate Tissues.
abstract: An increasing number of BET family protein inhibitors have recently entered clinical trials. It has been reported that attempts of monitoring target engagement of the BET bromodomain inhibitor OTX015 using literature-described putative pharmacodynamic markers, such as c-Myc, BRD2, etc., failed to detect pharmacodynamic marker responses in AML patients treated at active dose and those with clinical responses. Here, we report the identification and characterization of HEXIM1 and other genes as robust pharmacodynamic markers for BET inhibitors. Global gene expression profiling studies were carried out using cancer cells and surrogate tissues, such as whole blood and skin, to identify genes that are modulated by BET family proteins. Candidate markers were further characterized for concentration- and time-dependent responses to the BET inhibitor ABBV-075 in vitro and in vivo HEXIM1 was found to be the only gene that exhibited robust and consistent modulation by BET inhibitors across multiple cancer indications and surrogate tissues. Markers such as SERPINI1, ZCCHC24, and ZMYND8 were modulated by ABBV-075 and other BET inhibitors across cancer cell lines and xenograft tumors but not in blood and skin. Significant downregulation of c-Myc, a well-publicized target of BET inhibitors, was largely restricted to hematologic cancer cell lines. Incorporating well-characterized pharmacodynamic markers, such as HEXIM1 and other genes described here, can provide a better understanding of potential efficacy and toxicity associated with inhibiting BET family proteins and informs early clinical decisions on BET inhibitor development programs. Mol Cancer Ther; 16(2); 388-96. ©2016 AACR.
authors.affiliation: Oncology Discovery, AbbVie Inc., North Chicago, Illinois. xiaoyu.lin@abbvie.com yu.shen@abbvie.com.
authors.forename: Xiaoyu
authors.initials: X
authors.lastname: Lin
authors.affiliation: Oncology Discovery, AbbVie Inc., North Chicago, Illinois.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Huang
authors.affiliation: Oncology Discovery, AbbVie Inc., North Chicago, Illinois.
authors.forename: Tamar
authors.initials: T
authors.lastname: Uziel
authors.affiliation: Oncology Discovery, AbbVie Inc., North Chicago, Illinois.
authors.forename: Paul
authors.initials: P
authors.lastname: Hessler
authors.affiliation: Oncology Discovery, AbbVie Inc., North Chicago, Illinois.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Albert
authors.affiliation: Oncology Discovery, AbbVie Inc., North Chicago, Illinois.
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Roberts-Rapp
authors.affiliation: Oncology Discovery, AbbVie Inc., North Chicago, Illinois.
authors.forename: Keith F
authors.initials: KF
authors.lastname: McDaniel
authors.affiliation: Oncology Discovery, AbbVie Inc., North Chicago, Illinois.
authors.forename: Warren M
authors.initials: WM
authors.lastname: Kati
authors.affiliation: Oncology Discovery, AbbVie Inc., North Chicago, Illinois. xiaoyu.lin@abbvie.com yu.shen@abbvie.com.
authors.forename: Yu
authors.initials: Y
authors.lastname: Shen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D015415:Biomarkers; D001706:Biopsy; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors*; D009928:Organ Specificity / Q000235:genetics; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D014157:Transcription Factors; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; C476123:HEXIM1 protein, human; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D014157:Transcription Factors