title: Modeling RAS phenotype in colorectal cancer uncovers novel molecular traits of RAS dependency and improves prediction of response to targeted agents in patients.
abstract: OBJECTIVE
  KRAS wild-type status is an imperfect predictor of sensitivity to anti-EGF receptor (EGFR) monoclonal antibodies in colorectal cancer, motivating efforts to identify novel molecular aberrations driving RAS. This study aimed to build a quantitative readout of RAS pathway activity to (i) uncover molecular surrogates of RAS activity specific to colorectal cancer, (ii) improve the prediction of cetuximab response in patients, and (iii) suggest new treatment strategies.
  
  
  METHODS
  A model of RAS pathway activity was trained in a large colorectal cancer dataset and validated in three independent colorectal cancer patient datasets. Novel molecular traits were inferred from The Cancer Genome Atlas colorectal cancer data. The ability of the RAS model to predict resistance to cetuximab was tested in mouse xenografts and three independent patient cohorts. Drug sensitivity correlations between our model and large cell line compendiums were performed.
  
  
  RESULTS
  The performance of the RAS model was remarkably robust across three validation datasets. (i) Our model confirmed the heterogeneity of the RAS phenotype in KRAS wild-type patients, and suggests novel molecular traits driving its phenotype (e.g., MED12 loss, FBXW7 mutation, MAP2K4 mutation). (ii) It improved the prediction of response and progression-free survival (HR, 2.0; P < 0.01) to cetuximab compared with KRAS mutation (xenograft and patient cohorts). (iii) Our model consistently predicted sensitivity to MAP-ERK kinase (MEK) inhibitors (P < 0.01) in two cell panel screens.
  
  
  CONCLUSIONS
  Modeling the RAS phenotype in colorectal cancer allows for the robust interrogation of RAS pathway activity across cell lines, xenografts, and patient cohorts. It demonstrates clinical utility in predicting response to anti-EGFR agents and MEK inhibitors.
authors.affiliation: Sage Bionetworks (non-profit research organization), Fred-Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Justin
authors.initials: J
authors.lastname: Guinney
authors.affiliation: Sage Bionetworks (non-profit research organization), Fred-Hutchinson Cancer Research Center, Seattle, WA.|Department of Medical Oncology, Gustave Roussy, Villejuif, France.|INSERM U981, Université Paris XI, Villejuif, France.
authors.forename: Charles
authors.initials: C
authors.lastname: Ferté
authors.affiliation: AstraZeneca, London, UK.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Dry
authors.affiliation: AstraZeneca, London, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: McEwen
authors.affiliation: INSERM UMR-S775, Université Paris Descartes, Sorbonne Paris Cité, Paris France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Manceau
authors.affiliation: Koo Foundation Sun-Yat-Sen Cancer Center, Taipei, Taiwan.
authors.forename: K J
authors.initials: KJ
authors.lastname: Kao
authors.affiliation: Koo Foundation Sun-Yat-Sen Cancer Center, Taipei, Taiwan.
authors.forename: Kai-Ming
authors.initials: KM
authors.lastname: Chang
authors.affiliation: AstraZeneca, London, UK.
authors.forename: Claus
authors.initials: C
authors.lastname: Bendtsen
authors.affiliation: AstraZeneca, London, UK.
authors.forename: Kevin
authors.initials: K
authors.lastname: Hudson
authors.affiliation: Sage Bionetworks (non-profit research organization), Fred-Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Erich
authors.initials: E
authors.lastname: Huang
authors.affiliation: AstraZeneca, London, UK.
authors.forename: Brian
authors.initials: B
authors.lastname: Dougherty
authors.affiliation: Department of Medical Oncology, Gustave Roussy, Villejuif, France.|INSERM U981, Université Paris XI, Villejuif, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Ducreux
authors.affiliation: Department of Medical Oncology, Gustave Roussy, Villejuif, France.|INSERM U981, Université Paris XI, Villejuif, France.
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.affiliation: Sage Bionetworks (non-profit research organization), Fred-Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Friend
authors.affiliation: Sage Bionetworks (non-profit research organization), Fred-Hutchinson Cancer Research Center, Seattle, WA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Derry
authors.affiliation: INSERM UMR-S775, Université Paris Descartes, Sorbonne Paris Cité, Paris France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D015870:Gene Expression; D006801:Humans; D053208:Kaplan-Meier Estimate; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051379:Mice; D008957:Models, Genetic; D058990:Molecular Targeted Therapy; D020125:Mutation, Missense; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D011518:Proto-Oncogene Proteins; D020930:MAP Kinase Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins; D000068818:Cetuximab