The gamma secretase inhibitor MRK-003 attenuates pancreatic cancer growth in preclinical models

Masamichi Mizuma, Zeshaan A. Rasheed, Shinichi Yabuuchi, Noriyuki Omura, Nathaniel R. Campbell, Roeland F. De Wilde, Elizabeth De Oliveira, Qing Zhang, Oscar Puig, William Matsui, Manuel Hidalgo, Anirban Maitra, N. V. Rajeshkumar

Research output: Contribution to journalArticle

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy, with most patients facing an adverse clinical outcome. Aberrant Notch pathway activation has been implicated in the initiation and progression of PDAC, specifically the aggressive phenotype of the disease. We used a panel of human PDAC cell lines as well as patient-derived PDAC xenografts to determine whether pharmacologic targeting of Notch pathway could inhibit PDAC growth and potentiate gemcitabine sensitivity. MRK-003, a potent and selective γ-secretase inhibitor, treatment resulted in the downregulation of nuclear Notch1 intracellular domain, inhibition of anchorage-independent growth, and reduction of tumor-initiating cells capable of extensive self-renewal. Pretreatment of PDAC cells with MRK-003 in cell culture significantly inhibited the subsequent engraftment in immunocompromised mice. MRK-003 monotherapy significantly blocked tumor growth in 5 of 9 (56%) PDAC xenografts. A combination of MRK-003 and gemcitabine showed enhanced antitumor effects compared with gemcitabine in 4 of 9 (44%) PDAC xenografts, reduced tumor cell proliferation, and induced both apoptosis and intratumoral necrosis. Gene expression analysis of untreated tumors indicated that upregulation of NF-κB pathway components was predictive of sensitivity to MRK-003, whereas upregulation in B-cell receptor signaling and nuclear factor erythroid-derived 2-like 2 pathway correlated with response to the combination of MRK-003 with gemcitabine. Our findings strengthen the rationale for small-molecule inhibition of Notch signaling as a therapeutic strategy in PDAC.

Original languageEnglish (US)
Pages (from-to)1999-2009
Number of pages11
JournalMolecular Cancer Therapeutics
Volume11
Issue number9
DOIs
StatePublished - Sep 2012

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Amyloid Precursor Protein Secretases
Pancreatic Neoplasms
gemcitabine
Adenocarcinoma
Growth
Heterografts
Neoplasms
Up-Regulation
MRK 003
Neoplastic Stem Cells
Cytoplasmic and Nuclear Receptors
B-Lymphocytes
Necrosis
Down-Regulation
Cell Culture Techniques
Cell Proliferation
Apoptosis
Phenotype
Gene Expression
Cell Line

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Mizuma, M., Rasheed, Z. A., Yabuuchi, S., Omura, N., Campbell, N. R., De Wilde, R. F., ... Rajeshkumar, N. V. (2012). The gamma secretase inhibitor MRK-003 attenuates pancreatic cancer growth in preclinical models. Molecular Cancer Therapeutics, 11(9), 1999-2009. https://doi.org/10.1158/1535-7163.MCT-12-0017

The gamma secretase inhibitor MRK-003 attenuates pancreatic cancer growth in preclinical models. / Mizuma, Masamichi; Rasheed, Zeshaan A.; Yabuuchi, Shinichi; Omura, Noriyuki; Campbell, Nathaniel R.; De Wilde, Roeland F.; De Oliveira, Elizabeth; Zhang, Qing; Puig, Oscar; Matsui, William; Hidalgo, Manuel; Maitra, Anirban; Rajeshkumar, N. V.

In: Molecular Cancer Therapeutics, Vol. 11, No. 9, 09.2012, p. 1999-2009.

Research output: Contribution to journalArticle

Mizuma, M, Rasheed, ZA, Yabuuchi, S, Omura, N, Campbell, NR, De Wilde, RF, De Oliveira, E, Zhang, Q, Puig, O, Matsui, W, Hidalgo, M, Maitra, A & Rajeshkumar, NV 2012, 'The gamma secretase inhibitor MRK-003 attenuates pancreatic cancer growth in preclinical models', Molecular Cancer Therapeutics, vol. 11, no. 9, pp. 1999-2009. https://doi.org/10.1158/1535-7163.MCT-12-0017
Mizuma, Masamichi ; Rasheed, Zeshaan A. ; Yabuuchi, Shinichi ; Omura, Noriyuki ; Campbell, Nathaniel R. ; De Wilde, Roeland F. ; De Oliveira, Elizabeth ; Zhang, Qing ; Puig, Oscar ; Matsui, William ; Hidalgo, Manuel ; Maitra, Anirban ; Rajeshkumar, N. V. / The gamma secretase inhibitor MRK-003 attenuates pancreatic cancer growth in preclinical models. In: Molecular Cancer Therapeutics. 2012 ; Vol. 11, No. 9. pp. 1999-2009.
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