Oncotarget

Research Papers:

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

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 and Yubin Ge _

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Oncotarget. 2017; 8:44295-44311. https://doi.org/10.18632/oncotarget.17869

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Abstract

Changwen Ning1, Min Liang1, Shuang Liu1, Guan Wang1, Holly Edwards2,3, Yang Xia4, Lisa Polin2,3, Gregory Dyson2, Jeffrey W. Taub3,5,6, Ramzi M. Mohammad2,3, Asfar S. Azmi2,3, Lijing Zhao7 and Yubin Ge2,3,5

1National Engineering Laboratory for AIDS Vaccine, Key Laboratory for Molecular Enzymology and Engineering of the Ministry of Education, School of Life Sciences, Jilin University, Changchun, P.R. China

2Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA

3Molecular Therapeutics Program, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA

4Department of Pathology, The Second Hospital of Jilin University, Changchun, P.R. China

5Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA

6Division of Pediatric Hematology/Oncology, Children’s Hospital of Michigan, Detroit, MI, USA

7Department of Rehabilitation, School of Nursing, Jilin University, Changchun, P.R. China

Correspondence to:

Yubin Ge, email: [email protected]

Lijing Zhao, email: [email protected]

Keywords: pancreatic cancer, PI3K/mTOR, ERK, VS-5584, SCH772984

Received: March 29, 2017     Accepted: May 01, 2017     Published: May 15, 2017

ABSTRACT

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


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