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.

Document Type

Article

Publication Date

6-28-2024

Notes/Citation Information

0304-3835/© 2024 Elsevier B.V. All rights reserved.

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.canlet.2024.216919

Funding Information

This study was supported by the National Institutes of Health (NIH) grant R01CA208272 and O’Neal Invests grant from the Richard A. Elkus Foundation and the University of Alabama at Birmingham O’Neal Comprehensive Cancer Center (K.J.Y.). The funding source had no role in the study design, data collection, analysis and interpretation, and writing of the manuscript.

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