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The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models

Oncogene volume 35, pages 833–845 (2016)Cite this article

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Abstract

The primary aim of this study was to evaluate the antitumor efficacy of the bromodomain inhibitor JQ1 in pancreatic ductal adenocarcinoma (PDAC) patient-derived xenograft (tumorgraft) models. A secondary aim of the study was to evaluate whether JQ1 decreases expression of the oncogene c-Myc in PDAC tumors, as has been reported for other tumor types. We used five PDAC tumorgraft models that retain specific characteristics of tumors of origin to evaluate the antitumor efficacy of JQ1. Tumor-bearing mice were treated with JQ1 (50 mg/kg daily for 21 or 28 days). Expression analyses were performed with tumors harvested from host mice after treatment with JQ1 or vehicle control. An nCounter PanCancer Pathways Panel (NanoString Technologies) of 230 cancer-related genes was used to identify gene products affected by JQ1. Quantitative RT–PCR, immunohistochemistry and immunoblots were carried out to confirm that changes in RNA expression reflected changes in protein expression. JQ1 inhibited the growth of all five tumorgraft models (P<0.05), each of which harbors a KRAS mutation; but induced no consistent change in expression of c-Myc protein. Expression profiling identified CDC25B, a regulator of cell cycle progression, as one of the three RNA species (TIMP3, LMO2 and CDC25B) downregulated by JQ1 (P<0.05). Inhibition of tumor progression was more closely related to decreased expression of nuclear CDC25B than to changes in c-Myc expression. JQ1 and other agents that inhibit the function of proteins with bromodomains merit further investigation for treating PDAC tumors. Work is ongoing in our laboratory to identify effective drug combinations that include JQ1.

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Acknowledgements

We thank Drs Donald J Buchsbaum, William E Grizzle, Mary-Ann Bjornsti and Christopher Klug for their insightful guidance and helpful discussions. This research was supported in part by UAB/UMN SPORE in pancreatic cancer (P50 CA101955).

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  1. J P Arnoletti

    Present address: 8Current address: Florida Hospital Orlando and University of Central Florida, Orlando, FL, USA.,

Authors and Affiliations

  1. Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, USA

    P L Garcia, A L Miller, K M Kreitzburg, T L Gamblin & K J Yoon

  2. Division of Anatomic Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

    L N Council & C A Hanna

  3. Division of General Surgery, Department of Surgery, Gastrointestinal Surgery or Surgical Oncology, University of Alabama at Birmingham, Birmingham, AL, USA

    J D Christein, M J Heslin, J P Arnoletti & J H Richardson

  4. Division of Preventive Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA

    D Chen

  5. Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL, USA

    S L Cramer

  6. Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA

    E S Yang

  7. Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA, USA

    J Qi & J E Bradner

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Correspondence to K J Yoon.

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Competing interests

James E Bradner and DFCI founded Tensha Therapeutics to develop derivatives of JQ1 and similar molecules for cancer therapy.

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Garcia, P., Miller, A., Kreitzburg, K. et al. The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models. Oncogene 35, 833–845 (2016). https://doi.org/10.1038/onc.2015.126

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