PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab

Minaxi Jhawer, Sanjay Goel, Andrew J. Wilson, Cristina Montagna, Yi He Ling, Do Sun Byun, Shannon Nasser, Diego Arango, Joongho Shin, Lidija Klampfer, Leonard H. Augenlicht, Roman Perez-Soler, John M. Mariadason

Research output: Contribution to journalArticle

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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 G0-G1 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.

Original languageEnglish (US)
Pages (from-to)1953-1961
Number of pages9
JournalCancer Research
Volume68
Issue number6
DOIs
StatePublished - Mar 15 2008

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Epidermal Growth Factor Receptor
Colonic Neoplasms
Mutation
Cell Line
Growth
Cetuximab
HCT116 Cells
Gene Dosage
Epidermal Growth Factor
Colorectal Neoplasms
Colon
Biomarkers
Monoclonal Antibodies
Apoptosis
Messenger RNA

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. / Jhawer, Minaxi; Goel, Sanjay; Wilson, Andrew J.; Montagna, Cristina; Ling, Yi He; Byun, Do Sun; Nasser, Shannon; Arango, Diego; Shin, Joongho; Klampfer, Lidija; Augenlicht, Leonard H.; Perez-Soler, Roman; Mariadason, John M.

In: Cancer Research, Vol. 68, No. 6, 15.03.2008, p. 1953-1961.

Research output: Contribution to journalArticle

Jhawer, Minaxi ; Goel, Sanjay ; Wilson, Andrew J. ; Montagna, Cristina ; Ling, Yi He ; Byun, Do Sun ; Nasser, Shannon ; Arango, Diego ; Shin, Joongho ; Klampfer, Lidija ; Augenlicht, Leonard H. ; Perez-Soler, Roman ; Mariadason, John M. / PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab. In: Cancer Research. 2008 ; Vol. 68, No. 6. pp. 1953-1961.
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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 G0-G1 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.",
author = "Minaxi Jhawer and Sanjay Goel and Wilson, {Andrew J.} and Cristina Montagna and Ling, {Yi He} and Byun, {Do Sun} and Shannon Nasser and Diego Arango and Joongho Shin and Lidija Klampfer and Augenlicht, {Leonard H.} and Roman Perez-Soler and Mariadason, {John M.}",
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T1 - PIK3CA mutation/PTEN expression status predicts response of colon cancer cells to the epidermal growth factor receptor inhibitor cetuximab

AU - Jhawer, Minaxi

AU - Goel, Sanjay

AU - Wilson, Andrew J.

AU - Montagna, Cristina

AU - Ling, Yi He

AU - Byun, Do Sun

AU - Nasser, Shannon

AU - Arango, Diego

AU - Shin, Joongho

AU - Klampfer, Lidija

AU - Augenlicht, Leonard H.

AU - Perez-Soler, Roman

AU - Mariadason, John M.

PY - 2008/3/15

Y1 - 2008/3/15

N2 - 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 G0-G1 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.

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 G0-G1 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.

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