Targeted inhibition of Src kinase signaling attenuates pancreatic tumorigenesis

Nagaraj Nagathihalli, J. Joshua Smith, Frank Revetta, M. Kay Washington, Nipun Merchant

Research output: Contribution to journalArticle

74 Citations (Scopus)

Abstract

Elevated Src expression correlates with malignant potential and metastatic disease in many tumors including pancreatic cancer. We sought to characterize the molecular effects of Src kinase inhibition with dasatinib (BMS-354825), a novel, multitargeted kinase inhibitor that targets Src family kinases in pancreatic ductal adenocarcinoma (PDA).We identified sensitive and resistant PDA cell lines to dasatinib treatment and tested the molecular effects of Src inhibition in vitro and in vivo.We show for the first time that cellular localization of Src expression affects survival in patients with PDA. Pancreatic tumors with increased membranous expression of Src resulted in decreased survival compared with tumors that had increased cytoplasmic Src expression. Src kinase inhibition with dasatinib markedly inhibits cell proliferation, migration, invasion, cell cycle progression and anchorage-independent growth, and stimulates apoptosis. This was accompanied by decreased phosphorylation of Src, focal adhesion kinase, paxillin, AKT, signal transducers and activators of transcription 3 (STAT3), extracellular signal-regulated kinase, and mitogen-activated protein kinase (MAPK), as well as decreased cyclin D1 expression in a time- and concentration-dependent manner. Furthermore, small interfering RNA to Src results in a significant decrease in cell proliferation, invasion, and migration of pancreatic cancer cells. Dasatinib treatment also inhibits in vivo pancreatic tumor growth. Mechanisms of resistance to Src inhibition seem to be related to a lack of inhibition of STAT3 and MAPK signaling. These results establish a mechanistic rationale for Src inhibition with dasatinib as a therapeutic target in the treatment of pancreatic cancer and identify potential biomarkers of resistance to Src inhibition.

Original languageEnglish (US)
Pages (from-to)2322-2332
Number of pages11
JournalMolecular Cancer Therapeutics
Volume9
Issue number8
DOIs
StatePublished - Aug 2010
Externally publishedYes

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src-Family Kinases
Carcinogenesis
Pancreatic Neoplasms
STAT3 Transcription Factor
Adenocarcinoma
Mitogen-Activated Protein Kinases
Cell Movement
Neoplasms
Cell Proliferation
Paxillin
Focal Adhesion Protein-Tyrosine Kinases
Survival
Cyclin D1
Extracellular Signal-Regulated MAP Kinases
Therapeutics
Growth
Small Interfering RNA
Dasatinib
Cell Cycle
Phosphotransferases

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Targeted inhibition of Src kinase signaling attenuates pancreatic tumorigenesis. / Nagathihalli, Nagaraj; Smith, J. Joshua; Revetta, Frank; Washington, M. Kay; Merchant, Nipun.

In: Molecular Cancer Therapeutics, Vol. 9, No. 8, 08.2010, p. 2322-2332.

Research output: Contribution to journalArticle

Nagathihalli, Nagaraj ; Smith, J. Joshua ; Revetta, Frank ; Washington, M. Kay ; Merchant, Nipun. / Targeted inhibition of Src kinase signaling attenuates pancreatic tumorigenesis. In: Molecular Cancer Therapeutics. 2010 ; Vol. 9, No. 8. pp. 2322-2332.
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