The BET bromodomain inhibitor JQ1 suppresses growth of pancreatic ductal adenocarcinoma in patient-derived xenograft models

Abstract

The primary aim of this study was to evaluate the antitumor efficacy of the bromodomain inhibitor JQ1 in pancreatic ductal adenocarcinoma (PDAC) patient-derived xenograft (tumorgraft) models. A secondary aim of the study was to evaluate whether JQ1 decreases expression of the oncogene c-Myc in PDAC tumors, as has been reported for other tumor types. We used five PDAC tumorgraft models that retain specific characteristics of tumors of origin to evaluate the antitumor efficacy of JQ1. Tumor-bearing mice were treated with JQ1 (50 mg/kg daily for 21 or 28 days). Expression analyses were performed with tumors harvested from host mice after treatment with JQ1 or vehicle control. An nCounter PanCancer Pathways Panel (NanoString Technologies) of 230 cancer-related genes was used to identify gene products affected by JQ1. Quantitative RT-PCR, immunohistochemistry and immunoblots were carried out to confirm that changes in RNA expression reflected changes in protein expression. JQ1 inhibited the growth of all five tumorgraft models (P<0.05), each of which harbors a KRAS mutation; but induced no consistent change in expression of c-Myc protein. Expression profiling identified CDC25B, a regulator of cell cycle progression, as one of the three RNA species (TIMP3, LMO2 and CDC25B) downregulated by JQ1 (P<0.05). Inhibition of tumor progression was more closely related to decreased expression of nuclear CDC25B than to changes in c-Myc expression. JQ1 and other agents that inhibit the function of proteins with bromodomains merit further investigation for treating PDAC tumors. Work is ongoing in our laboratory to identify effective drug combinations that include JQ1.

BET inhibitors block pancreatic stellate cell collagen I production and attenuate fibrosis in vivo

“…Since BET inhibitors significantly decrease collagen I expression by primary cancer-associated PSCs, our results suggest that JQ1 may also block PDAC progression indirectly by decreasing collagen I-rich ECM deposition. Importantly, JQ1 can also directly limit growth of PDAC cells in vitro in patient-derived xenograft models and in transgenic mouse models (19,21,22,34). Our findings that JQ1 decreases ADM development in the EL-Kras G12D mouse model in vivo are in agreement with the report showing that JQ1 decreases ADM in ex vivo acinar cultures and in the PdxCre/LSL-Kras (KC) mouse model (21).…”

Concepts to Target MYC in Pancreatic Cancer

“…Although MYC mRNA levels were slightly decreased upon the treatment with JQ1 in vivo, no regulation of MYC protein expression was described (54). In contrast, expression of the cell-cycle regulator CDC25B (cell division cycle 25B) was diminished, and this molecular event closely correlated with therapeutic efficacy (54), arguing that CDC25B is the relevant BET-I-sensitive driver in the investigated model. In addition to the human PdX models, JQ1 activity was recently demonstrated in a genetically engineered PDAC mouse model (GEMM).…”

“…In human PDAC patient-derived xenotransplants (PdX), JQ1 showed activity (54). It was demonstrated that JQ1 reduced proliferation and a distinct reduction in tumor growth in 4 of 5 individual subcutaneous PdX models (54). Although MYC mRNA levels were slightly decreased upon the treatment with JQ1 in vivo, no regulation of MYC protein expression was described (54).…”

“…However, JQ1 controls MYC not in all of the investigated PDAC cell lines, and here, FOSL1 and HMGA2 (high-mobility group AT-hook 2) were shown to be additional oncogenic drivers downregulated upon BET inhibition (53). In human PDAC patient-derived xenotransplants (PdX), JQ1 showed activity (54). It was demonstrated that JQ1 reduced proliferation and a distinct reduction in tumor growth in 4 of 5 individual subcutaneous PdX models (54).…”

“…It was demonstrated that JQ1 reduced proliferation and a distinct reduction in tumor growth in 4 of 5 individual subcutaneous PdX models (54). Although MYC mRNA levels were slightly decreased upon the treatment with JQ1 in vivo, no regulation of MYC protein expression was described (54). In contrast, expression of the cell-cycle regulator CDC25B (cell division cycle 25B) was diminished, and this molecular event closely correlated with therapeutic efficacy (54), arguing that CDC25B is the relevant BET-I-sensitive driver in the investigated model.…”