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

Niranjan Awasthi, David Kronenberger, Alexis Stefaniak, Md Sazzad Hassan, Urs von Holzen, Margaret Schwarz, Roderich E. Schwarz

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)41-49
Number of pages9
JournalCancer Letters
Volume459
DOIs
StatePublished - Sep 10 2019

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gemcitabine
Pancreatic Neoplasms
Phosphatidylinositol 3-Kinases
Drug Therapy
Adenocarcinoma
Heterografts
Neoplasms
Growth
130-nm albumin-bound paclitaxel
Survival
Therapeutics

Keywords

  • Combination therapy
  • MEK inhibitor
  • Nab-paclitaxel
  • Pancreatic cancer
  • Trametinib

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Dual inhibition of the PI3K and MAPK pathways enhances nab-paclitaxel/gemcitabine chemotherapy response in preclinical models of pancreatic cancer. / Awasthi, Niranjan; Kronenberger, David; Stefaniak, Alexis; Hassan, Md Sazzad; von Holzen, Urs; Schwarz, Margaret; Schwarz, Roderich E.

In: Cancer Letters, Vol. 459, 10.09.2019, p. 41-49.

Research output: Contribution to journalArticle

Awasthi, Niranjan ; Kronenberger, David ; Stefaniak, Alexis ; Hassan, Md Sazzad ; von Holzen, Urs ; Schwarz, Margaret ; Schwarz, Roderich E. / Dual inhibition of the PI3K and MAPK pathways enhances nab-paclitaxel/gemcitabine chemotherapy response in preclinical models of pancreatic cancer. In: Cancer Letters. 2019 ; Vol. 459. pp. 41-49.
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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.",
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