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.
Highlights
The 5 year survival rate for patients with pancreatic cancer (PC) has remained at less than 10% for decades
We proposed that JQ1-induced cell cycle arrest, coincident with increases in levels of DNA damage, would sensitize pancreatic ductal adenocarcinoma (PDAC) tumor cells to gemcitabine
We proposed that JQ1-induced cell cycle arrest, coincident wit5hofin15
Summary
The 5 year survival rate for patients with pancreatic cancer (PC) has remained at less than 10% for decades. The remaining 80% of patients undergo chemotherapy ± radiation [1] Combination regimens such as FOLFIRINOX and gemcitabine + nab-paclitaxel are used to treat pancreatic ductal adenocarcinoma (PDAC), the most common type of PC, but are useful only in a subset of patients with good performance status, due to the toxicity of these regimens [2,3,4]. Paclitaxel causes a G2/M cell cycle arrest and potentiates gemcitabine. This combination is commonly used for the treatment of patients with several types of solid tumors. Agents that increase levels of DNA damage, either by inducing damage or by inhibiting DNA repair, augment the efficacy of gemcitabine. Recent literature focuses on combining gemcitabine with other targeted agents such as inhibitors of CDK4, Wee, ATR, PLK1, or Aurora B kinase, to effect cell cycle dysregulation [10,11,12,13,14,15]
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