The BET Inhibitor JQ1 Augments the Antitumor Efficacy of Gemcitabine in Preclinical Models of Pancreatic Cancer

Abstract

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.

The BRD4 inhibitor JQ1 suppresses tumor growth by reducing c-Myc expression in endometrial cancer

“…JQ1 has been reported to cause human neuroblastoma cell cycle arrest in G1 phase mainly by inhibiting the MYCN and mTOR signaling pathways [ 22 ]. JQ1 also decreases the proportion of cells in G2 phase and increases the share of cells in G1 phase in a preclinical model of pancreatic cancer [ 23 ]. Our investigation of the mechanism of JQ1 showed that treatment with JQ1 alone significantly downregulated the expression levels of CDC25A, CyclinD1, and CDK4, inhibited the activity of Rb, and upregulated the expression of P21, a cell cycle-related factor that mainly suppresses the activity of CDK2/CDK4.…”

The BET Inhibitor JQ1 Potentiates the Anticlonogenic Effect of Radiation in Pancreatic Cancer Cells

“…We showed previously that JQ1 decreased expression of DNA repair proteins Ku80 and RAD51 in in vivo PDAC models ( 18 ). We also reported that JQ1 increased levels of DNA damage, as reflected by an increase in levels of the damage marker γH2AX ( 18 , 23 ). These observations suggested that JQ1 interferes with DNA damage repair.…”

Combination of anlotinib and gemcitabine promotes the G0/G1 cell cycle arrest and apoptosis of intrahepatic cholangiocarcinoma in vitro

“…Blockchain extension also exerts its anti‐tumor activity through a series of other cellular mechanisms on DNA synthesis. 18 , 19 Anlotinib is a multi‐target drug; however, the purpose of this study was to investigate the anti‐tumor mechanism of anlotinib combined with gemcitabine. To determine whether the inhibitory effect of anlotinib combined with gemcitabine on cell growth inhibition was due to cell cycle arrest, we analyzed the cell cycle distribution of these cells using FCM with PI/RNase staining.…”