title: Sensitivity of KRAS-Mutant Colorectal Cancers to Combination Therapy That Cotargets MEK and CDK4/6.
abstract: OBJECTIVE
  The emerging need for rational combination treatment approaches led us to test the concept that cotargeting MEK and CDK4/6 would prove efficacious in KRAS-mutant (KRAS(mt)) colorectal cancers, where upregulated CDK4 and hyperphosphorylated retinoblastoma (RB) typify the vast majority of tumors.
  
  
  METHODS
  Initial testing was carried out in the HCT-116 tumor model, which is known to harbor a KRAS mutation. Efficacy studies were then performed with five RB(+) patient-derived colorectal xenograft models, genomically diverse with respect to KRAS, BRAF, and PIK3CA mutational status. Tolerance, efficacy, and pharmacodynamic evaluation of target modulation were evaluated in response to daily dosing with either agent alone or concurrent coadministration.
  
  
  RESULTS
  Synergy was observed in vitro when HCT-116 cells were treated over a broad range of doses of trametinib and palbociclib. Subsequent in vivo evaluation of this model showed a higher degree of antitumor activity resulting from the combination compared to that achievable with single-agent treatment. Testing of colorectal patient-derived xenograft (PDX) models further showed that combination of trametinib and palbociclib was well tolerated and resulted in objective responses in all KRAS(mt) models tested. Stasis was observed in a KRAS/BRAF wild-type and a BRAF(mt) model.
  
  
  CONCLUSIONS
  Combination of trametinib and palbociclib was well tolerated and highly efficacious in all three KRAS-mutant colorectal cancer PDX models tested. Promising preclinical activity seen here supports clinical evaluation of this treatment approach to improve therapeutic outcome for patients with metastatic colorectal cancer.
authors.affiliation: Translational Oncology Program, University of Michigan Medical School, Ann Arbor, Michigan. Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Elizabeth K
authors.initials: EK
authors.lastname: Ziemke
authors.affiliation: Translational Oncology Program, University of Michigan Medical School, Ann Arbor, Michigan. Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Dosch
authors.affiliation: Translational Oncology Program, University of Michigan Medical School, Ann Arbor, Michigan. Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Joel D
authors.initials: JD
authors.lastname: Maust
authors.affiliation: Translational Oncology Program, University of Michigan Medical School, Ann Arbor, Michigan. Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Amrith
authors.initials: A
authors.lastname: Shettigar
authors.affiliation: Department of Family Medicine, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Ananda
authors.initials: A
authors.lastname: Sen
authors.affiliation: Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Theodore H
authors.initials: TH
authors.lastname: Welling
authors.affiliation: Department of Surgery, University of Michigan Medical School, Ann Arbor, Michigan.
authors.forename: Karin M
authors.initials: KM
authors.lastname: Hardiman
authors.affiliation: Translational Oncology Program, University of Michigan Medical School, Ann Arbor, Michigan. Department of Radiology, University of Michigan Medical School, Ann Arbor, Michigan. Department of Pharmacology, University of Michigan Medical School, Ann Arbor, Michigan. jssl@med.umich.edu.
authors.forename: Judith S
authors.initials: JS
authors.lastname: Sebolt-Leopold
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics*; D051358:Cyclin-Dependent Kinase 4 / Q000235:genetics*; D051361:Cyclin-Dependent Kinase 6 / Q000235:genetics*; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D045325:HCT116 Cells; D006801:Humans; D020935:MAP Kinase Signaling System / Q000235:genetics*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation / Q000187:drug effects / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*
chemical_list: C117307:KRAS protein, human; D019869:Phosphatidylinositol 3-Kinases; D048493:Proto-Oncogene Proteins B-raf; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D016283:Proto-Oncogene Proteins p21(ras)