PMID- 18339877
OWN - NLM
STAT- MEDLINE
DCOM- 20080409
LR  - 20221102
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 68
IP  - 6
DP  - 2008 Mar 15
TI  - PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to 
      the epidermal growth factor receptor inhibitor cetuximab.
PG  - 1953-61
LID - 10.1158/0008-5472.CAN-07-5659 [doi]
AB  - 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.
FAU - Jhawer, Minaxi
AU  - Jhawer M
AD  - Department of Oncology, Montefiore Medical Center, Albert Einstein Cancer Center, 
      Bronx, NY 10467, USA.
FAU - Goel, Sanjay
AU  - Goel S
FAU - Wilson, Andrew J
AU  - Wilson AJ
FAU - Montagna, Cristina
AU  - Montagna C
FAU - Ling, Yi-He
AU  - Ling YH
FAU - Byun, Do-Sun
AU  - Byun DS
FAU - Nasser, Shannon
AU  - Nasser S
FAU - Arango, Diego
AU  - Arango D
FAU - Shin, Joongho
AU  - Shin J
FAU - Klampfer, Lidija
AU  - Klampfer L
FAU - Augenlicht, Leonard H
AU  - Augenlicht LH
FAU - Perez-Soler, Roman
AU  - Perez-Soler R
FAU - Mariadason, John M
AU  - Mariadason JM
LA  - eng
GR  - R01 CA123316/CA/NCI NIH HHS/United States
PT  - Journal Article
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Antibodies, Monoclonal, Humanized)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Quinazolines)
RN  - 0 (RNA, Messenger)
RN  - 62229-50-9 (Epidermal Growth Factor)
RN  - DA87705X9K (Erlotinib Hydrochloride)
RN  - EC 2.7.1.- (Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases)
RN  - EC 2.7.1.137 (PIK3CA protein, human)
RN  - EC 2.7.10.1 (ErbB Receptors)
RN  - EC 2.7.11.1 (BRAF protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
RN  - EC 3.1.3.67 (PTEN Phosphohydrolase)
RN  - EC 3.1.3.67 (PTEN protein, human)
RN  - EC 3.6.5.2 (ras Proteins)
RN  - PQX0D8J21J (Cetuximab)
SB  - IM
EIN - Cancer Res. 2008 Aug 15;68(16):6859. Soler, Roman Perez [corrected to 
      Perez-Soler, Roman]
EIN - Cancer Res. 2009 Dec 1;69(23):9156
MH  - Antibodies, Monoclonal/*pharmacology
MH  - Antibodies, Monoclonal, Humanized
MH  - Antineoplastic Agents/*pharmacology
MH  - Cell Line, Tumor
MH  - Cetuximab
MH  - Class I Phosphatidylinositol 3-Kinases
MH  - Colonic Neoplasms/*drug therapy/genetics/metabolism/pathology
MH  - Epidermal Growth Factor/pharmacology
MH  - ErbB Receptors/biosynthesis/genetics/metabolism
MH  - Erlotinib Hydrochloride
MH  - G1 Phase/drug effects
MH  - Gene Dosage
MH  - Genes, ras
MH  - HCT116 Cells
MH  - Humans
MH  - MAP Kinase Signaling System
MH  - *Mutation
MH  - PTEN Phosphohydrolase/*biosynthesis
MH  - Phosphatidylinositol 3-Kinases/*genetics
MH  - Proto-Oncogene Proteins B-raf/genetics
MH  - Quinazolines/pharmacology
MH  - RNA, Messenger/biosynthesis/genetics
MH  - Resting Phase, Cell Cycle/drug effects
MH  - ras Proteins/genetics
PMC - PMC3972216
MID - NIHMS545797
EDAT- 2008/03/15 09:00
MHDA- 2008/04/10 09:00
PMCR- 2014/04/01
CRDT- 2008/03/15 09:00
PHST- 2008/03/15 09:00 [pubmed]
PHST- 2008/04/10 09:00 [medline]
PHST- 2008/03/15 09:00 [entrez]
PHST- 2014/04/01 00:00 [pmc-release]
AID - 68/6/1953 [pii]
AID - 10.1158/0008-5472.CAN-07-5659 [doi]
PST - ppublish
SO  - Cancer Res. 2008 Mar 15;68(6):1953-61. doi: 10.1158/0008-5472.CAN-07-5659.