Abstract 2449: The bromodomain inhibitor JQ1 blocks growth of pancreatic cancer cells in 3D collagen.

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is associated with a pronounced collagen-rich stromal reaction that has been shown to contribute to chemo-resistance. We have found that the collagen microenvironment promotes expression of histone acetyltransferases (HATs) and thereby promotes chemo-resistance; however, HATs have proven to be difficult ‘druggable’ targets. Bromodomain proteins are chromatin readers that can bind to acetylated histones and thereby regulate gene expression. JQ1, an inhibitor of BET class of human bromodomains, was shown to have efficacy against leukemia and lymphoma cell lines. Thus, we examined the effect of JQ1 on a panel of PDAC cells grown in 3D collagen. AsPC1, CD18 and Panc02.03 cells were particularly sensitive to the effects of JQ1, while Panc1 cells were relatively resistant to JQ1 treatment. JQ1 decreased myc mRNA and increased p21 mRNA in CD18 cells, but not in Panc1 cells. JQ1 also decreased growth of chemo-resistant CD18 cells grown in 3D collagen, and blocked EGF and TGF-β1-induced growth and scattering of Panc1 and CD18 cells in 3D collagen. The MEK1/2 inhibitor U0126 and JQ1 synergistically attenuated growth of CD18 and Panc1 cells in 3D collagen. In addition, EGFR inhibitors (AG1478 and PD153035) and JQ1 also synergistically attenuated the growth of CD18 and Panc1 cells in 3D collagen. In contrast, the p38 MAPK inhibitor SB202190 did not attenuate the effect of JQ1 on growth of CD18 and Panc1 cells in 3D collagen. Finally, JQ1 potentiated the effect of gemcitabine on the growth of CD18 and Panc1 cells in 3D collagen. Overall, these results suggest that JQ1 and other bromodomain inhibitors are potential therapeutic agents for the treatment of pancreatic cancer. Citation Format: Vaibhav Sahai, Krishan Kumar, Kazumi Ebine, Halla Nimeiri, Hidayatullah G. Munshi. The bromodomain inhibitor JQ1 blocks growth of pancreatic cancer cells in 3D collagen. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2449. doi:10.1158/1538-7445.AM2013-2449