TY - JOUR
T1 - BET inhibition decreases HMGCS2 and sensitizes resistant pancreatic tumors to gemcitabine
AU - Miller, Aubrey L.
AU - Fehling, Samuel C.
AU - Vance, Rebecca B.
AU - Chen, Dongquan
AU - Brown, Eric Josh
AU - Hossain, M. Iqbal
AU - Heard, Eric O.
AU - Andrabi, Shaida A.
AU - Wang, Hengbin
AU - Yang, Eddy S.
AU - Buchsbaum, Donald J.
AU - van Waardenburg, Robert C.A.M.
AU - Bellis, Susan L.
AU - Yoon, Karina J.
N1 - Publisher Copyright:
© 2024 Elsevier B.V.
PY - 2024/6/28
Y1 - 2024/6/28
N2 - 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.
AB - 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.
KW - BET bromodomain inhibitor (BETi)
KW - Gemcitabine resistance (gemR)
KW - HMG-CoA synthase 2 (HMGCS2)
KW - Pancreatic cancer
KW - Patient-derived xenograft (PDX) models
UR - http://www.scopus.com/inward/record.url?scp=85192277495&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85192277495&partnerID=8YFLogxK
U2 - 10.1016/j.canlet.2024.216919
DO - 10.1016/j.canlet.2024.216919
M3 - Article
C2 - 38704133
AN - SCOPUS:85192277495
SN - 0304-3835
VL - 592
JO - Cancer Letters
JF - Cancer Letters
M1 - 216919
ER -
