title: PI3KCA/PTEN deregulation contributes to impaired responses to cetuximab in metastatic colorectal cancer patients.
abstract: BACKGROUND
  It has been reported that KRAS mutations (and to a lesser extent KRAS mutations with the BRAF V600E mutation) negatively affect response to anti-epidermal growth factor receptor (EGFR) mAbs in metastatic colorectal cancer (mCRC) patients, while the biological impact of the EGFR pathway represented by PI3K/PTEN/AKT on anti-EGFR treatment is still not clear.
  
  
  METHODS
  We analysed formalin-fixed samples from a cohort of 32 mCRC patients treated with cetuximab by means of EGFR immunohistochemistry, EGFR and PTEN FISH analysis, and KRAS, BRAF, PI3KCA, and PTEN genomic sequencing.
  
  
  RESULTS
  Ten (31%) of 32 patients showed a partial response to cetuximab and 22 (69%) did not [nonresponder (NR)]. EGFR immunophenotype and FISH-based gene status did not predict an anti-EGFR mAb response, whereas KRAS mutations (24%) and PI3K pathway activation, by means of PI3KCA mutations (13%) or PTEN mutation (10%)/loss (13%), were significantly restricted to, respectively, 41% and 37% of NRs.
  
  
  CONCLUSIONS
  These findings suggested that KRAS mutations and PI3KCA/PTEN deregulation significantly correlate with resistance to cetuximab. In line with this, patients carrying KRAS mutations or with activated PI3K profiles can benefit from targeted treatments only by switching off molecules belonging to the downstream signalling of activated EGFR, such as mammalian target of rapamycin.
authors.affiliation: Experimental Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Perrone
authors.forename: A
authors.initials: A
authors.lastname: Lampis
authors.forename: M
authors.initials: M
authors.lastname: Orsenigo
authors.forename: M
authors.initials: M
authors.lastname: Di Bartolomeo
authors.forename: A
authors.initials: A
authors.lastname: Gevorgyan
authors.forename: M
authors.initials: M
authors.lastname: Losa
authors.forename: M
authors.initials: M
authors.lastname: Frattini
authors.forename: C
authors.initials: C
authors.lastname: Riva
authors.forename: S
authors.initials: S
authors.lastname: Andreola
authors.forename: E
authors.initials: E
authors.lastname: Bajetta
authors.forename: L
authors.initials: L
authors.lastname: Bertario
authors.forename: E
authors.initials: E
authors.lastname: Leo
authors.forename: M A
authors.initials: MA
authors.lastname: Pierotti
authors.forename: S
authors.initials: S
authors.lastname: Pilotti
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004252:DNA Mutational Analysis; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D018773:Genes, erbB-1 / Q000502:physiology; D011905:Genes, ras; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000502:physiology; D009362:Neoplasm Metastasis; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D009687:Nuclear Proteins; C503859:PI3KCA protein, human; D014157:Transcription Factors; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D000068818:Cetuximab