Targeting ERK enhances the cytotoxic effect of the novel PI3K and mTOR dual inhibitor VS-5584 in preclinical models of pancreatic cancer

• DOI: 10.18632/oncotarget.17869
• Publication Date: 2017-05-24T15:14:38Z
• Authors: Changwen Ning; Min Liang; Shuang Liu; Guan Wang; Holly Edwards; Yang Xia; Lisa Polin; Gregory Dyson; Jeffrey W. Taub; Ramzi M. Mohammad; Asfar S. Azmi; Lijing Zhao; Yubin Ge
• Keywords: 0301 basic medicine; Dose-Response Relationship, Drug; Cell Survival; Morpholines; Cell Cycle; Drug Evaluation, Preclinical; Antineoplastic Agents; Drug Synergism; 3. Good health; Pancreatic Neoplasms; Disease Models, Animal; Mice; Phosphatidylinositol 3-Kinases; 03 medical and health sciences; Genes, ras; Cell Movement; Drug Resistance, Neoplasm; Cell Line, Tumor; Animals; Humans; Phosphorylation; Extracellular Signal-Regulated MAP Kinases; Research Paper; Phosphoinositide-3 Kinase Inhibitors

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease in urgent need of newer therapeutic modalities. Majority patients with PDAC have mutations KRAS, which unfortunately remains an ineffectual target. Our strategy here to target KRAS downstream effectors PI3K and mTOR. In this study, we investigated the antitumor efficacy novel mTOR dual inhibitor VS-5584 PDAC. data shows that PI3K/mTOR inhibition causes ERK activation all tested cell lines. Although MEK GSK1120212 could abrogate VS-5584-induced activation, it did not substantially enhance death lines tested. However, combination SCH772984 only mitigated but also enhanced death. xenograft model PDAC, observed 28% 44% tumor for individual treatment SCH772984, respectively, while combined showed superior (80%) compared vehicle control treatment. findings support clinical development