2. Academic Validation
  3. BET inhibition decreases HMGCS2 and sensitizes resistant pancreatic tumors to gemcitabine

BET inhibition decreases HMGCS2 and sensitizes resistant pancreatic tumors to gemcitabine

  • Cancer Lett. 2024 May 3:592:216919. doi: 10.1016/j.canlet.2024.216919.
Aubrey L Miller 1,  Samuel C Fehling 1,  Rebecca B Vance 1,  Dongquan Chen 2,  Eric Josh Brown 1,  M Iqbal Hossain 1,  Eric O Heard 1,  Shaida A Andrabi 3,  Hengbin Wang 4,  Eddy S Yang 5,  Donald J Buchsbaum 6,  Robert C A M van Waardenburg 1,  Susan L Bellis 7,  Karina J Yoon 8
Affiliations

Affiliations

  • 1 Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 2 Department of Preventive Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 3 Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, USA; Department of Neurology, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 4 Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 5 Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 6 Department of Obstetrics and Gynecology, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 7 Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 8 Department of Pharmacology and Toxicology, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: kyoon@uab.edu.
PMID: 38704133 DOI: 10.1016/j.canlet.2024.216919
Abstract

Efforts to develop targetable molecular bases for drug resistance for pancreatic ductal adenocarcinoma (PDAC) have been equivocally successful. Using RNA-seq and ingenuity pathway analysis we identified that the superpathway of Cholesterol biosynthesis is upregulated in gemcitabine resistant (gemR) tumors using a unique PDAC PDX model with resistance to gemcitabine acquired in vivo. Analysis of additional in vitro and in vivo gemR PDAC models showed that HMG-CoA synthase 2 (HMGCS2), an Enzyme involved in Cholesterol biosynthesis and rate limiting in ketogenesis, is overexpressed in these models. Mechanistic data demonstrate the novel findings that HMGCS2 contributes to gemR and confers metastatic properties in PDAC models, and that HMGCS2 is BRD4 dependent. Further, BET inhibitor JQ1 decreases levels of HMGCS2, sensitizes PDAC cells to gemcitabine, and a combination of gemcitabine and JQ1 induced regressions of gemR tumors in vivo. Our data suggest that decreasing HMGCS2 may reverse gemR, and that HMGCS2 represents a useful therapeutic target for treating gemcitabine resistant PDAC.

Keywords

BET bromodomain inhibitor (BETi); Gemcitabine resistance (gemR); HMG-CoA synthase 2 (HMGCS2); Pancreatic cancer; Patient-derived xenograft (PDX) models.

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