Gemcitabine is used to treat pancreatic cancer (PC), but is not curative. We sought to determine whether gemcitabine + a BET bromodomain inhibitor was superior to gemcitabine, and identify proteins that may contribute to the efficacy of this combination. This study was based on observations that cell cycle dysregulation and DNA damage augment the efficacy of gemcitabine. BET inhibitors arrest cells in G1 and allow increases in DNA damage, likely due to inhibition of expression of DNA repair proteins Ku80 and RAD51. BET inhibitors (JQ1 or I-BET762) + gemcitabine were synergistic in vitro, in Panc1, MiaPaCa2 and Su86 PC cell lines. JQ1 + gemcitabine was more effective in vivo than either drug alone in patient-derived xenograft models (P < 0.01). Increases in the apoptosis marker cleaved caspase 3 and DNA damage marker γH2AX paralleled antitumor efficacy. Notably, RNA-seq data showed that JQ1 + gemcitabine selectively inhibited HMGCS2 and APOC1 ~6-fold, compared to controls. These proteins contribute to cholesterol biosynthesis and lipid metabolism, and their overexpression supports tumor cell proliferation. IPA data indicated that JQ1 + gemcitabine selectively inhibited the LXR/RXR activation pathway, suggesting the hypothesis that this inhibition may contribute to the observed in vivo efficacy of JQ1 + gemcitabine.
|State||Published - Jul 2 2021|
Bibliographical noteFunding Information:
Funding: This work was supported by the National Institutes of Health (National Cancer Institute) grants R01 CA208272 (K.J.Y.). A.L.M. was a recipient of the predoctoral training fellowshop in Cell and Molecular Biology (CMB) T32 training grant (2017–2018).
This work was supported by the National Institutes of Health (National Cancer Institute) grants R01 CA208272 (K.J.Y.). A.L.M. was a recipient of the predoctoral training fellowshop in Cell and Molecular Biology (CMB) T32 training grant (2017?2018). Acknowledgments: The authors thank Mike Crowley at UAB Heflin Center for performing RNAsequencing. Conflicts of Interest: E.S.Y. serves as an advisory board/consultant for AstraZeneca, Bayer, Clovis, and Strata Oncology and received grant support from Eli Lilly and PUMA Biotechnologies, Inc. The other authors report no potential conflict of interest.
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
- BET bromodomain inhibitor
- Combination therapy
- Pancreatic ductal adenocarcinoma
- Patient-derived xenograft
ASJC Scopus subject areas
- Cancer Research