Abstract 513: Investigating stress-response pathways in pancreatic cancer cells using novel PERK inhibitors

Abstract

Abstract An adaptive stress response mechanism, termed the unfolded protein response (UPR), is highly activated in a variety of tumor types to cope with ER stress and maintain protein homeostasis. PERK (PKR-like endoplasmic reticulum kinase) is one of the key components of the UPR. PERK is a Ser/Thr protein kinase whose active homodimer phosphorylates and inactivates eukaryotic initiation factor 2α (eIF2α), thereby inhibiting protein translation globally and reducing the load of newly synthesized proteins entering the ER. Previous studies demonstrated that cells with a compromised PERK signaling pathway are sensitive to hypoxic stress in vitro and form tumors that grow more slowly in vivo. Thus, selective inhibitors of PERK activity may be useful therapeutic candidates for the treatment of cancer. Using an HTS approach a number of lead compounds were identified with demonstrated ability to inhibit PERK kinase activity in vitro. The potent PERK inhibitors were further tested in pancreatic cancer cells to evaluate the modulation of the PERK-eIF2α-ATF4-CHOP signaling pathway. The effect of PERK inhibitors on cell viability was determined by an MTS assay. PERK inhibitors had dose-dependent effects on suppression of pancreatic cancer cell proliferation. Inhibitor-mediated PERK inhibition is associated with the down-regulation of PERK signaling and with the suppression of pancreatic cancer cell proliferation, suggesting their potential anticancer activities. Here we present new findings implicating additional inputs into this stress response. Citation Format: Jihyun Park, Qiantao Wang, Tamer S. Kaoud, Clint D. J Tavares, Ramakrishna Edupuganti, Pengyu Ren, Kevin N. Dalby. Investigating stress-response pathways in pancreatic cancer cells using novel PERK inhibitors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 513. doi:10.1158/1538-7445.AM2014-513