title: Additional value of EGFR downstream signaling phosphoprotein expression to KRAS status for response to anti-EGFR antibodies in colorectal cancer.
abstract: KRAS mutations are a strong predictive marker of resistance to anti-epidermal growth factor receptor (EGFR) antibodies in advanced colorectal cancer (CRC) but only a subset of wild-type (WT) KRAS patients are responders, suggesting the existence of additional markers of resistance to this treatment. The activation of EGFR downstream signaling pathways may be one of these ones. In a series of 42 patients with advanced CRC treated with cetuximab/panitumumab, for whom KRAS status was previously determined, we retrospectively analyzed the intratumor expression of EGFR downstream signaling phosphoproteins of the RAS/MAPK and PI3K/AKT pathways (pERK1/2, pMEK1, pAKT, pP70S6K and pGSK3beta) using Bio-Plex phosphoprotein array. Association with tumor response, progression-free survival (PFS) and overall survival (OS) was assessed. The expression of all the phosphoproteins was higher in KRAS mutated tumors than in WT tumors. The expression of pP70S6K was lower in responders than in nonresponder patients. In univariate analysis, patients with high pMEK1 or pP70S6K expression had a shorter PFS than those with low expression. Patients with high pP70S6K expression also had a shorter OS. In multivariate analysis, PFS was shorter for patients with high pMEK1 or pP70S6K expression, independently of KRAS status, as OS for patients with high pP70S6K expression. Therefore, WT KRAS patients with high pP70S6K expression had a shorter survival than those with low expression. Our results suggest the importance of EGFR downstream signaling phosphoproteins expression in addition to KRAS status to define the subgroup of patients who will not benefit from anti-EGFR therapy.
authors.affiliation: Institut National de la Recherche et de la Santé Médicale, UMR-S775, Paris, France.
authors.forename: Geraldine
authors.initials: G
authors.lastname: Perkins
authors.forename: Astrid
authors.initials: A
authors.lastname: Lièvre
authors.forename: Carole
authors.initials: C
authors.lastname: Ramacci
authors.forename: Tchao
authors.initials: T
authors.lastname: Méatchi
authors.forename: Aurélien
authors.initials: A
authors.lastname: de Reynies
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Emile
authors.forename: Valérie
authors.initials: V
authors.lastname: Boige
authors.forename: Gorana
authors.initials: G
authors.lastname: Tomasic
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Bachet
authors.forename: Fréderic
authors.initials: F
authors.lastname: Bibeau
authors.forename: Olivier
authors.initials: O
authors.lastname: Bouché
authors.forename: Frédérique
authors.initials: F
authors.lastname: Penault-Llorca
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Merlin
authors.forename: Pierre
authors.initials: P
authors.lastname: Laurent-Puig
mesh_terms: D000368:Aged; D000906:Antibodies / Q000276:immunology*; D058534:Class I Phosphatidylinositol 3-Kinases; D015179:Colorectal Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D018572:Disease-Free Survival; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism*; D005260:Female; D011905:Genes, ras; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010750:Phosphoproteins / Q000378:metabolism*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D015398:Signal Transduction
chemical_list: D000906:Antibodies; D010750:Phosphoproteins; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D066246:ErbB Receptors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf