Dual inhibition of the PI3K and MAPK pathways enhances nab-paclitaxel/gemcitabine chemotherapy response in preclinical models of pancreatic cancer

doi:10.1016/j.canlet.2019.05.037

. 2019 Sep 10:459:41-49.

doi: 10.1016/j.canlet.2019.05.037. Epub 2019 May 30.

Dual inhibition of the PI3K and MAPK pathways enhances nab-paclitaxel/gemcitabine chemotherapy response in preclinical models of pancreatic cancer

Niranjan Awasthi¹, David Kronenberger², Alexis Stefaniak³, Md Sazzad Hassan⁴, Urs von Holzen⁵, Margaret A Schwarz⁶, Roderich E Schwarz⁷

Affiliations

¹ Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA; Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46617, USA. Electronic address: nawasthi@iupui.edu.
² Department of Biological Sciences, University of Notre Dame, South Bend, IN 46617, USA.
³ Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA.
⁴ Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA; Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46617, USA.
⁵ Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA; Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46617, USA; Goshen Center for Cancer Care, Goshen, IN 46526 USA.
⁶ Department of Pediatrics, Indiana University School of Medicine, South Bend, IN 46617, USA; Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46617, USA.
⁷ Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA; Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46617, USA; Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA.

PMID: 31153980
DOI: 10.1016/j.canlet.2019.05.037

Dual inhibition of the PI3K and MAPK pathways enhances nab-paclitaxel/gemcitabine chemotherapy response in preclinical models of pancreatic cancer

Niranjan Awasthi et al. Cancer Lett. 2019.

. 2019 Sep 10:459:41-49.

doi: 10.1016/j.canlet.2019.05.037. Epub 2019 May 30.

Authors

Niranjan Awasthi¹, David Kronenberger², Alexis Stefaniak³, Md Sazzad Hassan⁴, Urs von Holzen⁵, Margaret A Schwarz⁶, Roderich E Schwarz⁷

Affiliations

¹ Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA; Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46617, USA. Electronic address: nawasthi@iupui.edu.
² Department of Biological Sciences, University of Notre Dame, South Bend, IN 46617, USA.
³ Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA.
⁴ Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA; Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46617, USA.
⁵ Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA; Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46617, USA; Goshen Center for Cancer Care, Goshen, IN 46526 USA.
⁶ Department of Pediatrics, Indiana University School of Medicine, South Bend, IN 46617, USA; Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46617, USA.
⁷ Department of Surgery, Indiana University School of Medicine, South Bend, IN 46617, USA; Harper Cancer Research Institute, University of Notre Dame, South Bend, IN 46617, USA; Roswell Park Comprehensive Cancer Center, Buffalo, NY 14203, USA.

PMID: 31153980
DOI: 10.1016/j.canlet.2019.05.037

Abstract

Standard chemotherapy for pancreatic ductal adenocarcinoma (PDAC), nab-paclitaxel (NPT) plus gemcitabine (Gem), has led to an average survival of 8.5 months. Presently, no therapeutics exist that effectively target the KRAS oncogene, activated in 95% of PDACs, but alternative strategies focus on inhibition of downstream effectors of KRAS signaling. Through combined inhibition of PI3K and MAPK signaling with MK-2206 (MK) and trametinib (Tra), enhancement of NPT + Gem response was evaluated. Median animal survival was significantly improved by the NPT + Gem combination (67% increase). Addition of MK-2206 or trametinib further increased median survival: NPT + Gem + MK (86%), NPT + Gem + Tra (105%), and NPT + Gem + MK + Tra (129%). In cell line-derived xenografts, the net tumor growth (in mm³) compared to controls (878.5) was significantly reduced by NPT + Gem (191.2), NPT + Gem + MK (150.7), NPT + Gem + Tra (62.2) and NPT + Gem + MK + Tra (49.9) therapies. In patient-derived xenografts, the combination of MK-2206 and trametinib with chemotherapy had an additive response in reducing tumor growth. Effects of therapy on tumor cell proliferation and apoptosis corresponded with tumor growth inhibition. These findings suggest that the standard chemotherapy response of PDAC can be enhanced through dual targeting of PI3K and MAPK signaling, which could lead to improved PDAC therapy.

Keywords: Combination therapy; MEK inhibitor; Nab-paclitaxel; Pancreatic cancer; Trametinib.

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Dual inhibition of the PI3K and MAPK pathways enhances nab-paclitaxel/gemcitabine chemotherapy response in preclinical models of pancreatic cancer

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Dual inhibition of the PI3K and MAPK pathways enhances nab-paclitaxel/gemcitabine chemotherapy response in preclinical models of pancreatic cancer

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