title: Rational combination of a MEK inhibitor, selumetinib, and the Wnt/calcium pathway modulator, cyclosporin A, in preclinical models of colorectal cancer.
abstract: OBJECTIVE
  The mitogen-activated protein kinase (MAPK) pathway is a crucial regulator of cell proliferation, survival, and resistance to apoptosis. MEK inhibitors are being explored as a treatment option for patients with KRAS-mutant colorectal cancer who are not candidates for EGFR-directed therapies. Initial clinical results of MEK inhibitors have yielded limited single-agent activity in colorectal cancer, indicating that rational combination strategies are needed.
  
  
  METHODS
  In this study, we conducted unbiased gene set enrichment analysis and synthetic lethality screens with selumetinib, which identified the noncanonical Wnt/Ca++ signaling pathway as a potential mediator of resistance to the MEK1/2 inhibitor selumetinib. To test this, we used shRNA constructs against relevant WNT receptors and ligands resulting in increased responsiveness to selumetinib in colorectal cancer cell lines. Further, we evaluated the rational combination of selumetinib and WNT pathway modulators and showed synergistic antiproliferative effects in in vitro and in vivo models of colorectal cancer.
  
  
  RESULTS
  Importantly, this combination not only showed tumor growth inhibition but also tumor regression in the more clinically relevant patient-derived tumor explant (PDTX) models of colorectal cancer. In mechanistic studies, we observed a trend toward increased markers of apoptosis in response to the combination of MEK and WntCa(++) inhibitors, which may explain the observed synergistic antitumor effects.
  
  
  CONCLUSIONS
  These results strengthen the hypothesis that targeting both the MEK and Wnt pathways may be a clinically effective rational combination strategy for patients with metastatic colorectal cancer.
authors.affiliation: Division of Medical Oncology, University of Colorado, Colorado, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Spreafico
authors.forename: John J
authors.initials: JJ
authors.lastname: Tentler
authors.forename: Todd M
authors.initials: TM
authors.lastname: Pitts
authors.forename: Aik Choon
authors.initials: AC
authors.lastname: Tan
authors.forename: Mark A
authors.initials: MA
authors.lastname: Gregory
authors.forename: John J
authors.initials: JJ
authors.lastname: Arcaroli
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Klauck
authors.forename: Martine C
authors.initials: MC
authors.lastname: McManus
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Hansen
authors.forename: Jihye
authors.initials: J
authors.lastname: Kim
authors.forename: Lindsey N
authors.initials: LN
authors.lastname: Micel
authors.forename: Heather M
authors.initials: HM
authors.lastname: Selby
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Newton
authors.forename: Kelly L
authors.initials: KL
authors.lastname: McPhillips
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Gustafson
authors.forename: James V
authors.initials: JV
authors.lastname: Degregori
authors.forename: Wells A
authors.initials: WA
authors.lastname: Messersmith
authors.forename: Robert A
authors.initials: RA
authors.lastname: Winn
authors.forename: S Gail
authors.initials: SG
authors.lastname: Eckhardt
mesh_terms: D017209:Apoptosis; D001562:Benzimidazoles / Q000008:administration & dosage*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016572:Cyclosporine / Q000008:administration & dosage*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011518:Proto-Oncogene Proteins / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras); D015398:Signal Transduction / Q000187:drug effects; D060449:Wnt Signaling Pathway / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics
chemical_list: C517975:AZD 6244; D001562:Benzimidazoles; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D016572:Cyclosporine; D020930:MAP Kinase Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D002118:Calcium