SCH66336, inhibitor of protein farnesylation, blocks signal transducer and activators of transcription 3 signaling in lung cancer and interacts with a small molecule inhibitor of epidermal growth factor receptor/human epidermal growth factor receptor 2

Afshin Dowlati, Amy Kluge, David Nethery, Balazs Halmos, Jeffrey A. Kern

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

Signal transducer and activators of transcription 3 (STAT3) is an important transcription factor that is essential for lung cancer cell survival. STAT3 is activated by diverse upstream receptor and nonreceptor tyrosine kinases, and blockade of STAT3 results in tumor growth inhibition. Therefore, a search for STAT3 inhibitors is under way. We demonstrate that SCH66336, at 4 μmol/l, completely blocks STAT3 phosphorlyation in a variety of nonsmall cell lung carcinoma (NSCLC) cell lines, whereas the effect on AKT and extracellular signal-regulated kinase activation is variable. Furthermore, SCH66336 has antiproliferative effects on NSCLC cells. When NSCLC cells are exposed sequentially to SCH66336 and a small molecule dual tyrosine kinase inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2, synergistic activity is observed with an increase in the fraction of cells undergoing apoptosis. Concurrent exposure to both agents is, however, associated with antagonism and decreased apoptosis. We conclude that blockade of STAT3 phosphorylation might be one of the mechanisms by which SCH66336 exerts its antitumor activity, and that this can be synergistic in vitro when administered sequentially with epidermal growth factor receptor inhibitors.

Original languageEnglish (US)
Pages (from-to)9-16
Number of pages8
JournalAnti-Cancer Drugs
Volume19
Issue number1
DOIs
StatePublished - Jan 2008
Externally publishedYes

Fingerprint

Protein Prenylation
STAT3 Transcription Factor
Epidermal Growth Factor Receptor
Lung Neoplasms
Carcinoma
Lung
Apoptosis
Extracellular Signal-Regulated MAP Kinases
Receptor Protein-Tyrosine Kinases
Protein-Tyrosine Kinases
lonafarnib
human ERBB2 protein
Cell Survival
Transcription Factors
Phosphorylation
Cell Line
Growth

Keywords

  • Epidermal growth factor receptor
  • Lung cancer
  • Signal transducer and activators of transcription 3

ASJC Scopus subject areas

  • Pharmacology
  • Cancer Research
  • Oncology

Cite this

@article{45a8cd27b0ee4330ad147e52276acf81,
title = "SCH66336, inhibitor of protein farnesylation, blocks signal transducer and activators of transcription 3 signaling in lung cancer and interacts with a small molecule inhibitor of epidermal growth factor receptor/human epidermal growth factor receptor 2",
abstract = "Signal transducer and activators of transcription 3 (STAT3) is an important transcription factor that is essential for lung cancer cell survival. STAT3 is activated by diverse upstream receptor and nonreceptor tyrosine kinases, and blockade of STAT3 results in tumor growth inhibition. Therefore, a search for STAT3 inhibitors is under way. We demonstrate that SCH66336, at 4 μmol/l, completely blocks STAT3 phosphorlyation in a variety of nonsmall cell lung carcinoma (NSCLC) cell lines, whereas the effect on AKT and extracellular signal-regulated kinase activation is variable. Furthermore, SCH66336 has antiproliferative effects on NSCLC cells. When NSCLC cells are exposed sequentially to SCH66336 and a small molecule dual tyrosine kinase inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2, synergistic activity is observed with an increase in the fraction of cells undergoing apoptosis. Concurrent exposure to both agents is, however, associated with antagonism and decreased apoptosis. We conclude that blockade of STAT3 phosphorylation might be one of the mechanisms by which SCH66336 exerts its antitumor activity, and that this can be synergistic in vitro when administered sequentially with epidermal growth factor receptor inhibitors.",
keywords = "Epidermal growth factor receptor, Lung cancer, Signal transducer and activators of transcription 3",
author = "Afshin Dowlati and Amy Kluge and David Nethery and Balazs Halmos and Kern, {Jeffrey A.}",
year = "2008",
month = "1",
doi = "10.1097/CAD.0b013e3282f1a908",
language = "English (US)",
volume = "19",
pages = "9--16",
journal = "Anti-Cancer Drugs",
issn = "0959-4973",
publisher = "Lippincott Williams and Wilkins",
number = "1",

}

TY - JOUR

T1 - SCH66336, inhibitor of protein farnesylation, blocks signal transducer and activators of transcription 3 signaling in lung cancer and interacts with a small molecule inhibitor of epidermal growth factor receptor/human epidermal growth factor receptor 2

AU - Dowlati, Afshin

AU - Kluge, Amy

AU - Nethery, David

AU - Halmos, Balazs

AU - Kern, Jeffrey A.

PY - 2008/1

Y1 - 2008/1

N2 - Signal transducer and activators of transcription 3 (STAT3) is an important transcription factor that is essential for lung cancer cell survival. STAT3 is activated by diverse upstream receptor and nonreceptor tyrosine kinases, and blockade of STAT3 results in tumor growth inhibition. Therefore, a search for STAT3 inhibitors is under way. We demonstrate that SCH66336, at 4 μmol/l, completely blocks STAT3 phosphorlyation in a variety of nonsmall cell lung carcinoma (NSCLC) cell lines, whereas the effect on AKT and extracellular signal-regulated kinase activation is variable. Furthermore, SCH66336 has antiproliferative effects on NSCLC cells. When NSCLC cells are exposed sequentially to SCH66336 and a small molecule dual tyrosine kinase inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2, synergistic activity is observed with an increase in the fraction of cells undergoing apoptosis. Concurrent exposure to both agents is, however, associated with antagonism and decreased apoptosis. We conclude that blockade of STAT3 phosphorylation might be one of the mechanisms by which SCH66336 exerts its antitumor activity, and that this can be synergistic in vitro when administered sequentially with epidermal growth factor receptor inhibitors.

AB - Signal transducer and activators of transcription 3 (STAT3) is an important transcription factor that is essential for lung cancer cell survival. STAT3 is activated by diverse upstream receptor and nonreceptor tyrosine kinases, and blockade of STAT3 results in tumor growth inhibition. Therefore, a search for STAT3 inhibitors is under way. We demonstrate that SCH66336, at 4 μmol/l, completely blocks STAT3 phosphorlyation in a variety of nonsmall cell lung carcinoma (NSCLC) cell lines, whereas the effect on AKT and extracellular signal-regulated kinase activation is variable. Furthermore, SCH66336 has antiproliferative effects on NSCLC cells. When NSCLC cells are exposed sequentially to SCH66336 and a small molecule dual tyrosine kinase inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2, synergistic activity is observed with an increase in the fraction of cells undergoing apoptosis. Concurrent exposure to both agents is, however, associated with antagonism and decreased apoptosis. We conclude that blockade of STAT3 phosphorylation might be one of the mechanisms by which SCH66336 exerts its antitumor activity, and that this can be synergistic in vitro when administered sequentially with epidermal growth factor receptor inhibitors.

KW - Epidermal growth factor receptor

KW - Lung cancer

KW - Signal transducer and activators of transcription 3

UR - http://www.scopus.com/inward/record.url?scp=36549089617&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=36549089617&partnerID=8YFLogxK

U2 - 10.1097/CAD.0b013e3282f1a908

DO - 10.1097/CAD.0b013e3282f1a908

M3 - Article

VL - 19

SP - 9

EP - 16

JO - Anti-Cancer Drugs

JF - Anti-Cancer Drugs

SN - 0959-4973

IS - 1

ER -