title: Inhibition of MEK and PI3K/mTOR suppresses tumor growth but does not cause tumor regression in patient-derived xenografts of RAS-mutant colorectal carcinomas.
abstract: OBJECTIVE
  Gene mutations along the Ras pathway (KRAS, NRAS, BRAF, PIK3CA) occur in approximately 50% of colorectal cancers (CRC) and correlate with poor response to anti-EGF receptor (EGFR) therapies. We assessed the effects of mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK) and phosphoinositide 3-kinase (PI3K)/mTOR inhibitors, which neutralize the major Ras effectors, in patient-derived xenografts from RAS/RAF/PIK3CA-mutant metastatic CRCs (mCRC).
  
  
  METHODS
  Forty mCRC specimens harboring KRAS, NRAS, BRAF, and/or PIK3CA mutations were implanted in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Each xenograft was expanded into four treatment arms: placebo, the MEK inhibitor AZD6244, the PI3K/mTOR inhibitor, BEZ235, or AZD6244 + BEZ235. Cases initially treated with placebo crossed over to AZD6244, BEZ235, and the anti-EGFR monoclonal antibody cetuximab.
  
  
  RESULTS
  At the 3-week evaluation time point, cotreatment of established tumors with AZD6244 + BEZ235 induced disease stabilization in the majority of cases (70%) but did not lead to overt tumor regression. Monotherapy was less effective, with BEZ235 displaying higher activity than AZD6244 (disease control rates, DCRs: AZD6244, 27.5%; BEZ235, 42.5%). Triple therapy with cetuximab provided further advantage (DCR, 88%). The extent of disease control declined at the 6-week evaluation time point (DCRs: AZD6244, 13.9%; BEZ235, 16.2%; AZD6244 + BEZ235, 34%). Cross-analysis of mice harboring xenografts from the same original tumor and treated with each of the different modalities revealed subgroups with preferential sensitivity to AZD6244 (12.5%), BEZ235 (35%), or AZD6244 + BEZ235 (42.5%); another subgroup (10%) showed equivalent response to any treatment.
  
  
  CONCLUSIONS
  The prevalent growth-suppressive effects produced by MEK and PI3K/mTOR inhibition suggest that this strategy may retard disease progression in patients. However, data offer cautionary evidence against the occurrence of durable responses.
authors.affiliation: Laboratory of Molecular Pharmacology, Institute for Cancer Research and Treatment (IRCC), Candiolo, Italy.
authors.forename: Giorgia
authors.initials: G
authors.lastname: Migliardi
authors.forename: Francesco
authors.initials: F
authors.lastname: Sassi
authors.forename: Davide
authors.initials: D
authors.lastname: Torti
authors.forename: Francesco
authors.initials: F
authors.lastname: Galimi
authors.forename: Eugenia R
authors.initials: ER
authors.lastname: Zanella
authors.forename: Michela
authors.initials: M
authors.lastname: Buscarino
authors.forename: Dario
authors.initials: D
authors.lastname: Ribero
authors.forename: Andrea
authors.initials: A
authors.lastname: Muratore
authors.forename: Paolo
authors.initials: P
authors.lastname: Massucco
authors.forename: Alberto
authors.initials: A
authors.lastname: Pisacane
authors.forename: Mauro
authors.initials: M
authors.lastname: Risio
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Capussotti
authors.forename: Silvia
authors.initials: S
authors.lastname: Marsoni
authors.forename: Federica
authors.initials: F
authors.lastname: Di Nicolantonio
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.forename: Paolo M
authors.initials: PM
authors.lastname: Comoglio
authors.forename: Livio
authors.initials: L
authors.lastname: Trusolino
authors.forename: Andrea
authors.initials: A
authors.lastname: Bertotti
mesh_terms: D019870:1-Phosphatidylinositol 4-Kinase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D016022:Case-Control Studies; D045744:Cell Line, Tumor; D003106:Colon / Q000378:metabolism / Q000473:pathology; D015179:Colorectal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005260:Female; D011905:Genes, ras; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000378:metabolism / Q000517:prevention & control* / Q000556:secondary; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000378:metabolism; D012007:Rectum / Q000378:metabolism / Q000473:pathology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; C546842:MTOR protein, human; D019870:1-Phosphatidylinositol 4-Kinase; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases