Transforming growth factor α expression drives constitutive epidermal growth factor receptor pathway activation and sensitivity to gefitinib (Iressa) in human pancreatic cancer cell lines

Maria S. Pino, Marissa Shrader, Cheryl H. Baker, Francesco Cognetti, Henry Q. Xiong, James L. Abbruzzese, David J. McConkey

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

The epidermal growth factor receptor (EGFR) is considered an important therapeutic target in pancreatic cancer, but it is currently impossible to identify those patients who are most likely to benefit from EGFR-directed therapy. We examined the biological effects of the EGFR tyrosine kinase inhibitor gefitinib (ZD1839, Iressa) in a panel of nine human pancreatic cancer cell lines. The drug strongly inhibited DNA synthesis and induced low levels of apoptosis at clinically relevant concentrations in a subset of three of the lines (L3.6p1, BxPC3, and Cfpac1). Sensitivity to gefitinib correlated directly with ligand [transforming growth factor-α (TGF-α)] expression (r2 = 0.71, P = 0.004) but not with surface EGFR expression. The gefitinib-sensitive cells displayed constitutive baseline EGFR phosphorylation, whereas the gefitinib-resistant cells did not. Exposure to gefitinib or a small interfering RNA construct specific for TGF-α reversed the constitutive EGFR phosphorylation and downstream target [extracellular signal-regulated kinases (ERK), AKT] phosphorylation in the gefitinib-sensitive cells but had no effects on ERK or AKT phosphorylation in gefitinib-resistant cells. Raseline EGFR phosphorylation was lower in a subclone of L3.6p1 selected for low TGF-α expression, and these cells were also resistant to gefitinib-mediated growth inhibition. Gefitinib blocked the growth of tumor xenografts derived from L3.6p1 cells but had no effect on the growth of tumors derived from EGFR-independent MiaPaCa-2 cells. Together, our data show that TGF-α expression identifies a subset of human pancreatic cancer cells that is dependent on EGFR signaling in vitro and in vivo. Quantification of TGF-α expression may therefore represent an effective means of identifying EGFR-responsive primary tumors.

Original languageEnglish
Pages (from-to)3802-3812
Number of pages11
JournalCancer Research
Volume66
Issue number7
DOIs
Publication statusPublished - Apr 1 2006

Fingerprint

Transforming Growth Factors
Pancreatic Neoplasms
Epidermal Growth Factor Receptor
Cell Line
Phosphorylation
Extracellular Signal-Regulated MAP Kinases
gefitinib
Growth
Neoplasms
Heterografts
Protein-Tyrosine Kinases
Small Interfering RNA
Apoptosis
Ligands

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Transforming growth factor α expression drives constitutive epidermal growth factor receptor pathway activation and sensitivity to gefitinib (Iressa) in human pancreatic cancer cell lines. / Pino, Maria S.; Shrader, Marissa; Baker, Cheryl H.; Cognetti, Francesco; Xiong, Henry Q.; Abbruzzese, James L.; McConkey, David J.

In: Cancer Research, Vol. 66, No. 7, 01.04.2006, p. 3802-3812.

Research output: Contribution to journalArticle

Pino, Maria S. ; Shrader, Marissa ; Baker, Cheryl H. ; Cognetti, Francesco ; Xiong, Henry Q. ; Abbruzzese, James L. ; McConkey, David J. / Transforming growth factor α expression drives constitutive epidermal growth factor receptor pathway activation and sensitivity to gefitinib (Iressa) in human pancreatic cancer cell lines. In: Cancer Research. 2006 ; Vol. 66, No. 7. pp. 3802-3812.
@article{76f356e3f345403fae49f0e99dcbfae3,
title = "Transforming growth factor α expression drives constitutive epidermal growth factor receptor pathway activation and sensitivity to gefitinib (Iressa) in human pancreatic cancer cell lines",
abstract = "The epidermal growth factor receptor (EGFR) is considered an important therapeutic target in pancreatic cancer, but it is currently impossible to identify those patients who are most likely to benefit from EGFR-directed therapy. We examined the biological effects of the EGFR tyrosine kinase inhibitor gefitinib (ZD1839, Iressa) in a panel of nine human pancreatic cancer cell lines. The drug strongly inhibited DNA synthesis and induced low levels of apoptosis at clinically relevant concentrations in a subset of three of the lines (L3.6p1, BxPC3, and Cfpac1). Sensitivity to gefitinib correlated directly with ligand [transforming growth factor-α (TGF-α)] expression (r2 = 0.71, P = 0.004) but not with surface EGFR expression. The gefitinib-sensitive cells displayed constitutive baseline EGFR phosphorylation, whereas the gefitinib-resistant cells did not. Exposure to gefitinib or a small interfering RNA construct specific for TGF-α reversed the constitutive EGFR phosphorylation and downstream target [extracellular signal-regulated kinases (ERK), AKT] phosphorylation in the gefitinib-sensitive cells but had no effects on ERK or AKT phosphorylation in gefitinib-resistant cells. Raseline EGFR phosphorylation was lower in a subclone of L3.6p1 selected for low TGF-α expression, and these cells were also resistant to gefitinib-mediated growth inhibition. Gefitinib blocked the growth of tumor xenografts derived from L3.6p1 cells but had no effect on the growth of tumors derived from EGFR-independent MiaPaCa-2 cells. Together, our data show that TGF-α expression identifies a subset of human pancreatic cancer cells that is dependent on EGFR signaling in vitro and in vivo. Quantification of TGF-α expression may therefore represent an effective means of identifying EGFR-responsive primary tumors.",
author = "Pino, {Maria S.} and Marissa Shrader and Baker, {Cheryl H.} and Francesco Cognetti and Xiong, {Henry Q.} and Abbruzzese, {James L.} and McConkey, {David J.}",
year = "2006",
month = "4",
day = "1",
doi = "10.1158/0008-5472.CAN-05-3753",
language = "English",
volume = "66",
pages = "3802--3812",
journal = "Journal of Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "7",

}

TY - JOUR

T1 - Transforming growth factor α expression drives constitutive epidermal growth factor receptor pathway activation and sensitivity to gefitinib (Iressa) in human pancreatic cancer cell lines

AU - Pino, Maria S.

AU - Shrader, Marissa

AU - Baker, Cheryl H.

AU - Cognetti, Francesco

AU - Xiong, Henry Q.

AU - Abbruzzese, James L.

AU - McConkey, David J.

PY - 2006/4/1

Y1 - 2006/4/1

N2 - The epidermal growth factor receptor (EGFR) is considered an important therapeutic target in pancreatic cancer, but it is currently impossible to identify those patients who are most likely to benefit from EGFR-directed therapy. We examined the biological effects of the EGFR tyrosine kinase inhibitor gefitinib (ZD1839, Iressa) in a panel of nine human pancreatic cancer cell lines. The drug strongly inhibited DNA synthesis and induced low levels of apoptosis at clinically relevant concentrations in a subset of three of the lines (L3.6p1, BxPC3, and Cfpac1). Sensitivity to gefitinib correlated directly with ligand [transforming growth factor-α (TGF-α)] expression (r2 = 0.71, P = 0.004) but not with surface EGFR expression. The gefitinib-sensitive cells displayed constitutive baseline EGFR phosphorylation, whereas the gefitinib-resistant cells did not. Exposure to gefitinib or a small interfering RNA construct specific for TGF-α reversed the constitutive EGFR phosphorylation and downstream target [extracellular signal-regulated kinases (ERK), AKT] phosphorylation in the gefitinib-sensitive cells but had no effects on ERK or AKT phosphorylation in gefitinib-resistant cells. Raseline EGFR phosphorylation was lower in a subclone of L3.6p1 selected for low TGF-α expression, and these cells were also resistant to gefitinib-mediated growth inhibition. Gefitinib blocked the growth of tumor xenografts derived from L3.6p1 cells but had no effect on the growth of tumors derived from EGFR-independent MiaPaCa-2 cells. Together, our data show that TGF-α expression identifies a subset of human pancreatic cancer cells that is dependent on EGFR signaling in vitro and in vivo. Quantification of TGF-α expression may therefore represent an effective means of identifying EGFR-responsive primary tumors.

AB - The epidermal growth factor receptor (EGFR) is considered an important therapeutic target in pancreatic cancer, but it is currently impossible to identify those patients who are most likely to benefit from EGFR-directed therapy. We examined the biological effects of the EGFR tyrosine kinase inhibitor gefitinib (ZD1839, Iressa) in a panel of nine human pancreatic cancer cell lines. The drug strongly inhibited DNA synthesis and induced low levels of apoptosis at clinically relevant concentrations in a subset of three of the lines (L3.6p1, BxPC3, and Cfpac1). Sensitivity to gefitinib correlated directly with ligand [transforming growth factor-α (TGF-α)] expression (r2 = 0.71, P = 0.004) but not with surface EGFR expression. The gefitinib-sensitive cells displayed constitutive baseline EGFR phosphorylation, whereas the gefitinib-resistant cells did not. Exposure to gefitinib or a small interfering RNA construct specific for TGF-α reversed the constitutive EGFR phosphorylation and downstream target [extracellular signal-regulated kinases (ERK), AKT] phosphorylation in the gefitinib-sensitive cells but had no effects on ERK or AKT phosphorylation in gefitinib-resistant cells. Raseline EGFR phosphorylation was lower in a subclone of L3.6p1 selected for low TGF-α expression, and these cells were also resistant to gefitinib-mediated growth inhibition. Gefitinib blocked the growth of tumor xenografts derived from L3.6p1 cells but had no effect on the growth of tumors derived from EGFR-independent MiaPaCa-2 cells. Together, our data show that TGF-α expression identifies a subset of human pancreatic cancer cells that is dependent on EGFR signaling in vitro and in vivo. Quantification of TGF-α expression may therefore represent an effective means of identifying EGFR-responsive primary tumors.

UR - http://www.scopus.com/inward/record.url?scp=33645748963&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33645748963&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-05-3753

DO - 10.1158/0008-5472.CAN-05-3753

M3 - Article

VL - 66

SP - 3802

EP - 3812

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0008-5472

IS - 7

ER -