Inhibition of the MEK/ERK pathway augments nab-paclitaxelbased chemotherapy effects in preclinical models of pancreatic cancer

Niranjan Awasthi, Sheena Monahan, Alexis Stefaniak, Margaret Schwarz, Roderich E. Schwarz

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

Nab-paclitaxel (NPT) combination with gemcitabine (Gem) represents the standard chemotherapy for pancreatic ductal adenocarcinoma (PDAC). Genetic alterations of the RAS/RAF/MEK/ERK (MAPK) signaling pathway yielding constitutive activation of the ERK cascade have been implicated as drivers of PDAC. Inhibition of downstream targets in the RAS-MAPK cascade such as MEK remains a promising therapeutic strategy. The efficacy of trametinib (Tra), a small molecule inhibitor of MEK1/2 kinase activity, in combination with nab-paclitaxel-based chemotherapy was evaluated in preclinical models of PDAC. The addition of trametinib to chemotherapy regimens showed a trend for an additive effect on tumor growth inhibition in subcutaneous AsPC-1 and Panc-1 PDAC xenografts. In a peritoneal dissemination model, median animal survival compared to controls (20 days) was increased after therapy with NPT (33 days, a 65% increase), Tra (31 days, a 55% increase), NPT+Tra (37 days, a 85% increase), NPT+Gem (39 days, a 95% increase) and NPT+Gem+Tra (49 days, a 145% increase). Effects of therapy on intratumoral proliferation and apoptosis corresponded with tumor growth inhibition. Trametinib effects were specifically accompanied by a decrease in phospho-ERK and an increase in cleaved caspase-3 and cleaved PARP-1 proteins. These findings suggest that the effects of nab-paclitaxel-based chemotherapy can be enhanced through specific inhibition of MEK1/2 kinase activity, and supports the clinical application of trametinib in combination with standard nab-paclitaxel-based chemotherapy in PDAC patients.

Original languageEnglish (US)
Pages (from-to)5274-5286
Number of pages13
JournalOncotarget
Volume9
Issue number4
DOIs
StatePublished - Jan 1 2018

Fingerprint

MAP Kinase Signaling System
Pancreatic Neoplasms
gemcitabine
Drug Therapy
Adenocarcinoma
Mitogen-Activated Protein Kinase Kinases
Phosphotransferases
130-nm albumin-bound paclitaxel
Growth
trametinib
Heterografts
Caspase 3
Neoplasms
Therapeutics
Apoptosis

Keywords

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

ASJC Scopus subject areas

  • Oncology

Cite this

Inhibition of the MEK/ERK pathway augments nab-paclitaxelbased chemotherapy effects in preclinical models of pancreatic cancer. / Awasthi, Niranjan; Monahan, Sheena; Stefaniak, Alexis; Schwarz, Margaret; Schwarz, Roderich E.

In: Oncotarget, Vol. 9, No. 4, 01.01.2018, p. 5274-5286.

Research output: Contribution to journalArticle

Awasthi, Niranjan ; Monahan, Sheena ; Stefaniak, Alexis ; Schwarz, Margaret ; Schwarz, Roderich E. / Inhibition of the MEK/ERK pathway augments nab-paclitaxelbased chemotherapy effects in preclinical models of pancreatic cancer. In: Oncotarget. 2018 ; Vol. 9, No. 4. pp. 5274-5286.
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abstract = "Nab-paclitaxel (NPT) combination with gemcitabine (Gem) represents the standard chemotherapy for pancreatic ductal adenocarcinoma (PDAC). Genetic alterations of the RAS/RAF/MEK/ERK (MAPK) signaling pathway yielding constitutive activation of the ERK cascade have been implicated as drivers of PDAC. Inhibition of downstream targets in the RAS-MAPK cascade such as MEK remains a promising therapeutic strategy. The efficacy of trametinib (Tra), a small molecule inhibitor of MEK1/2 kinase activity, in combination with nab-paclitaxel-based chemotherapy was evaluated in preclinical models of PDAC. The addition of trametinib to chemotherapy regimens showed a trend for an additive effect on tumor growth inhibition in subcutaneous AsPC-1 and Panc-1 PDAC xenografts. In a peritoneal dissemination model, median animal survival compared to controls (20 days) was increased after therapy with NPT (33 days, a 65{\%} increase), Tra (31 days, a 55{\%} increase), NPT+Tra (37 days, a 85{\%} increase), NPT+Gem (39 days, a 95{\%} increase) and NPT+Gem+Tra (49 days, a 145{\%} increase). Effects of therapy on intratumoral proliferation and apoptosis corresponded with tumor growth inhibition. Trametinib effects were specifically accompanied by a decrease in phospho-ERK and an increase in cleaved caspase-3 and cleaved PARP-1 proteins. These findings suggest that the effects of nab-paclitaxel-based chemotherapy can be enhanced through specific inhibition of MEK1/2 kinase activity, and supports the clinical application of trametinib in combination with standard nab-paclitaxel-based chemotherapy in PDAC patients.",
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