title: The gamma secretase inhibitor MRK-003 attenuates pancreatic cancer growth in preclinical models.
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.
authors: Departments of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
authors: Masamichi
authors: M
authors: Mizuma
authors: Zeshaan A
authors: ZA
authors: Rasheed
authors: Shinichi
authors: S
authors: Yabuuchi
authors: Noriyuki
authors: N
authors: Omura
authors: Nathaniel R
authors: NR
authors: Campbell
authors: Roeland F
authors: RF
authors: de Wilde
authors: Elizabeth
authors: E
authors: De Oliveira
authors: Qing
authors: Q
authors: Zhang
authors: Oscar
authors: O
authors: Puig
authors: William
authors: W
authors: Matsui
authors: Manuel
authors: M
authors: Hidalgo
authors: Anirban
authors: A
authors: Maitra
authors: N V
authors: NV
authors: Rajeshkumar
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D003499:Cyclic S-Oxides / Q000494:pharmacology* / Q000627:therapeutic use; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D004357:Drug Synergism; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013830:Thiadiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D059467:Transcriptome / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D003499:Cyclic S-Oxides; C523799:MRK 003; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D013830:Thiadiazoles; D003841:Deoxycytidine; D053829:Amyloid Precursor Protein Secretases; D000093542:Gemcitabine