title: Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS mutant colorectal cancer models.
abstract: OBJECTIVE
  Though the efficacy of MEK inhibitors is being investigated in KRAS-mutant colorectal cancers (CRC), early clinical trials of MEK inhibitor monotherapy did not reveal significant antitumor activity. Resistance to MEK inhibitor monotherapy developed through a variety of mechanisms converging in ERK reactivation. Since ERK increases cyclin D expression and increases entry into the cell cycle, we hypothesized that the combination of MEK inhibitors and CDK4/6 inhibitors would have synergistic antitumor activity and cause tumor regression in vivo.
  
  
  RESULTS
  The combination of MEK and CDK4/6 inhibitors synergistically inhibited cancer cell growth in vitro and caused tumor regression in vivo in cell line and patient-derived xenograft models. Combination therapy markedly decreased levels of phosphorylated ribosomal protein S6 both in vitro and in vivo and decreased Ki67 staining in vivo.
  
  
  METHODS
  We performed in vitro proliferation, colony formation, apoptosis, and senescence assays, and Western blots, on a panel of 11 KRAS mutant CRC cell lines treated with the MEK inhibitor MEK162, the CDK4/6 inhibitor palbociclib, or the combination. We also treated 4 KRAS mutant CRC cell line and patient-derived xenografts with the MEK inhibitor trametinib, the CDK4/6 inhibitor palbociclib, or the combination, and performed immunohistochemical and reverse phase protein array analysis.
  
  
  CONCLUSIONS
  Combined inhibition of both MEK and CDK4/6 is effective in preclinical models of KRAS mutant CRC and justifies a planned phase II clinical trial in patients with refractory KRAS-mutant CRC.Efficacy of the combination of MEK and CDK4/6 inhibitors in vitro and in vivo in KRAS mutant colorectal cancer models.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.|Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lee
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Helms
authors.affiliation: Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ningping
authors.initials: N
authors.lastname: Feng
authors.affiliation: Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Gay
authors.affiliation: Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Qing Edward
authors.initials: QE
authors.lastname: Chang
authors.affiliation: Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Tian
authors.affiliation: Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ji Y
authors.initials: JY
authors.lastname: Wu
authors.affiliation: Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Carlo
authors.initials: C
authors.lastname: Toniatti
authors.affiliation: Applied Cancer Science, University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Center for Co-Clinical Trials, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Heffernan
authors.affiliation: Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
authors.forename: Garth
authors.initials: G
authors.lastname: Powis
authors.affiliation: Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Lawrence N
authors.initials: LN
authors.lastname: Kwong
authors.affiliation: Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Kopetz
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002986:Clinical Trials as Topic; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D011905:Genes, ras; D006801:Humans; D048728:MAP Kinase Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D010879:Piperazines; D011725:Pyridines; C495900:CDK4 protein, human; C495911:CDK6 protein, human; C495902:Cdk4 protein, mouse; C495912:Cdk6 protein, mouse; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D048049:Extracellular Signal-Regulated MAP Kinases; D048728:MAP Kinase Kinase Kinase 1; C500026:palbociclib
keywords: CDK4/6 inhibitor; KRAS; MEK inhibitor; NRAS