title: Concomitant BRAF and PI3K/mTOR blockade is required for effective treatment of BRAF(V600E) colorectal cancer.
abstract: OBJECTIVE
  BRAF(V600E) mutations are associated with poor clinical prognosis in colorectal cancer (CRC). Although selective BRAF inhibitors are effective for treatment of melanoma, comparable efforts in CRC have been disappointing. Here, we investigated potential mechanisms underlying this resistance to BRAF inhibitors in BRAF(V600E) CRC.
  
  
  METHODS
  We examined phosphoinositide 3-kinase (PI3K)/mTOR signaling in BRAF(V600E) CRC cell lines after BRAF inhibition and cell viability and apoptosis after combined BRAF and PI3K/mTOR inhibition. We assessed the efficacy of in vivo combination treatment using a novel genetically engineered mouse model (GEMM) for BRAF(V600E) CRC.
  
  
  RESULTS
  Western blot analysis revealed sustained PI3K/mTOR signaling upon BRAF inhibition. Our BRAF(V600E) GEMM presented with sessile serrated adenomas/polyps, as seen in humans. Combination treatment in vivo resulted in induction of apoptosis and tumor regression.
  
  
  CONCLUSIONS
  We have established a novel GEMM to interrogate BRAF(V600E) CRC biology and identify more efficacious treatment strategies. Combination BRAF and PI3K/mTOR inhibitor treatment should be explored in clinical trials.
authors.affiliation: Division of Gastroenterology, Tufts Medical Center, Boston, Massachusetts 02111, USA.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Coffee
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Faber
authors.forename: Jatin
authors.initials: J
authors.lastname: Roper
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Sinnamon
authors.forename: Gautam
authors.initials: G
authors.lastname: Goel
authors.forename: Lily
authors.initials: L
authors.lastname: Keung
authors.forename: Wei Vivian
authors.initials: WV
authors.lastname: Wang
authors.forename: Loredana
authors.initials: L
authors.lastname: Vecchione
authors.forename: Veerle
authors.initials: V
authors.lastname: de Vriendt
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Weinstein
authors.forename: Roderick T
authors.initials: RT
authors.lastname: Bronson
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
authors.forename: Ramnik J
authors.initials: RJ
authors.lastname: Xavier
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
authors.forename: Eric S
authors.initials: ES
authors.lastname: Martin
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Hung
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D045325:HCT116 Cells; D006801:Humans; D007192:Indenes / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009374:Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D007192:Indenes; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D011720:Pyrazoles; D058570:TOR Serine-Threonine Kinases; C540167:2-(4-(1-(hydroxyimino)-2,3-dihydro-1H-inden-5-yl)-3-(pyridin-4-yl)-1H-pyrazol-1-yl)ethan-1-ol; C546842:MTOR protein, human; C482119:BRAF protein, human
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