title: PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab.
abstract: Cetuximab is a monoclonal antibody that targets the human epidermal growth factor receptor (EGFR). Although approved for use in EGFR-overexpressing advanced colorectal cancer, recent studies have shown a lack of association between EGFR overexpression and cetuximab response, requiring the identification of novel biomarkers predictive of response to this agent. To do so, 22 colon cancer cell lines were screened for cetuximab response in vitro and sensitive and resistant lines were identified. In sensitive cell lines, cetuximab induced a G(0)-G(1) arrest without inducing apoptosis. Notably, cetuximab-sensitive but not cetuximab-resistant cell lines were preferentially responsive to EGF-stimulated growth. Whereas neither EGFR protein/mRNA expression nor gene copy number correlated with cetuximab response, examination of the mutation status of signaling components downstream of EGFR showed that cell lines with activating PIK3CA mutations or loss of PTEN expression (PTEN null) were more resistant to cetuximab than PIK3CA wild type (WT)/PTEN-expressing cell lines (14 +/- 5.0% versus 38.5 +/- 6.4% growth inhibition, mean +/- SE; P = 0.008). Consistently, PIK3CA mutant isogenic HCT116 cells showed increased resistance to cetuximab compared with PIK3CA WT controls. Furthermore, cell lines that were PIK3CA mutant/PTEN null and Ras/BRAF mutant were highly resistant to cetuximab compared with those without dual mutations/PTEN loss (10.8 +/- 4.3% versus 38.8 +/- 5.9% growth inhibition, respectively; P = 0.002), indicating that constitutive and simultaneous activation of the Ras and PIK3CA pathways confers maximal resistance to this agent. A priori screening of colon tumors for PTEN expression status and PIK3CA and Ras/BRAF mutation status could help stratify patients likely to benefit from this therapy.
authors.affiliation: Department of Oncology, Montefiore Medical Center, Albert Einstein Cancer Center, Bronx, NY 10467, USA.
authors.forename: Minaxi
authors.initials: M
authors.lastname: Jhawer
authors.forename: Sanjay
authors.initials: S
authors.lastname: Goel
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Wilson
authors.forename: Cristina
authors.initials: C
authors.lastname: Montagna
authors.forename: Yi-He
authors.initials: YH
authors.lastname: Ling
authors.forename: Do-Sun
authors.initials: DS
authors.lastname: Byun
authors.forename: Shannon
authors.initials: S
authors.lastname: Nasser
authors.forename: Diego
authors.initials: D
authors.lastname: Arango
authors.forename: Joongho
authors.initials: J
authors.lastname: Shin
authors.forename: Lidija
authors.initials: L
authors.lastname: Klampfer
authors.forename: Leonard H
authors.initials: LH
authors.lastname: Augenlicht
authors.forename: Roman
authors.initials: R
authors.lastname: Perez-Soler
authors.forename: Roman Perez
authors.initials: RP
authors.lastname: Soler
authors.forename: John M
authors.initials: JM
authors.lastname: Mariadason
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000068818:Cetuximab; D058534:Class I Phosphatidylinositol 3-Kinases; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D000069347:Erlotinib Hydrochloride; D016193:G1 Phase / Q000187:drug effects; D018628:Gene Dosage; D011905:Genes, ras; D045325:HCT116 Cells; D006801:Humans; D020935:MAP Kinase Signaling System; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000096:biosynthesis*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D018631:ras Proteins / Q000235:genetics
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D011799:Quinazolines; D012333:RNA, Messenger; D004815:Epidermal Growth Factor; D000069347:Erlotinib Hydrochloride; 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; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D018631:ras Proteins; D000068818:Cetuximab