The src inhibitor AZD0530 blocks invasion and may act as a radiosensitizer in lung cancer cells

Phillip R. Purnell, Philip C. Mack, Clifford G. Tepper, Christopher P. Evans, Tim P. Green, Paul H. Gumerlock, Primo N. Lara, David R. Gandara, Hsing Jien Kung, Oliver Gautschi

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

With the emergence of Src inhibitors in clinical trials, improved knowledge of the molecular responses of cancer cells to these agents is warranted. This will facilitate the development of tests to identify patients who may benefit from these agents, allow drug activity to be monitored and rationalize the combination of these agents with other treatment modalities. Methods: This study evaluated the molecular and functional effects of Src inhibitor AZD0530 in human lung cancer cells, by Western blotting and reverse transcription- polymerase chain reaction, and by assays for cell viability, migration, and invasion. Results: Src was activated in four of five cell lines tested and the level corresponded with the invasive potential and the histologic subtype. Clinically relevant, submicromolar concentrations of AZD0530 blocked Src and focal adhesion kinase, resulting in significant inhibition of cell migration and Matrigel invasion. Reactivation of STAT3 and up-regulation of JAK indicated a potential mechanism of resistance. AZD0530 gave a potent and sustained blockage of AKT and enhanced the sensitivity to irradiation. Conclusions: The results indicated that AZD0530, aside from being a potent inhibitor of tumor cell invasion which could translate to inhibition of disease progression in the clinic, may also lower resistance of lung cancer cells to pro-apoptotic signals. copy; 2009 by the International Association for the Study of Lung Cancer.

Original languageEnglish
Pages (from-to)448-454
Number of pages7
JournalJournal of Thoracic Oncology
Volume4
Issue number4
DOIs
Publication statusPublished - Jan 1 2009
Externally publishedYes

Fingerprint

Lung Neoplasms
Cell Migration Assays
Cell Migration Inhibition
Focal Adhesion Protein-Tyrosine Kinases
Reverse Transcription
Disease Progression
Neoplasms
Cell Survival
Up-Regulation
Western Blotting
Clinical Trials
Cell Line
Polymerase Chain Reaction
saracatinib
Pharmaceutical Preparations
Therapeutics

Keywords

  • Invasion
  • Lung cancer
  • Metastasis
  • Protein kinase B
  • Signal transducer and activator of transcription
  • Src

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Purnell, P. R., Mack, P. C., Tepper, C. G., Evans, C. P., Green, T. P., Gumerlock, P. H., ... Gautschi, O. (2009). The src inhibitor AZD0530 blocks invasion and may act as a radiosensitizer in lung cancer cells. Journal of Thoracic Oncology, 4(4), 448-454. https://doi.org/10.1097/JTO.0b013e31819c78fb

The src inhibitor AZD0530 blocks invasion and may act as a radiosensitizer in lung cancer cells. / Purnell, Phillip R.; Mack, Philip C.; Tepper, Clifford G.; Evans, Christopher P.; Green, Tim P.; Gumerlock, Paul H.; Lara, Primo N.; Gandara, David R.; Kung, Hsing Jien; Gautschi, Oliver.

In: Journal of Thoracic Oncology, Vol. 4, No. 4, 01.01.2009, p. 448-454.

Research output: Contribution to journalArticle

Purnell, PR, Mack, PC, Tepper, CG, Evans, CP, Green, TP, Gumerlock, PH, Lara, PN, Gandara, DR, Kung, HJ & Gautschi, O 2009, 'The src inhibitor AZD0530 blocks invasion and may act as a radiosensitizer in lung cancer cells', Journal of Thoracic Oncology, vol. 4, no. 4, pp. 448-454. https://doi.org/10.1097/JTO.0b013e31819c78fb
Purnell, Phillip R. ; Mack, Philip C. ; Tepper, Clifford G. ; Evans, Christopher P. ; Green, Tim P. ; Gumerlock, Paul H. ; Lara, Primo N. ; Gandara, David R. ; Kung, Hsing Jien ; Gautschi, Oliver. / The src inhibitor AZD0530 blocks invasion and may act as a radiosensitizer in lung cancer cells. In: Journal of Thoracic Oncology. 2009 ; Vol. 4, No. 4. pp. 448-454.
@article{596438eb0e5d4da5b1b29c9a48708497,
title = "The src inhibitor AZD0530 blocks invasion and may act as a radiosensitizer in lung cancer cells",
abstract = "With the emergence of Src inhibitors in clinical trials, improved knowledge of the molecular responses of cancer cells to these agents is warranted. This will facilitate the development of tests to identify patients who may benefit from these agents, allow drug activity to be monitored and rationalize the combination of these agents with other treatment modalities. Methods: This study evaluated the molecular and functional effects of Src inhibitor AZD0530 in human lung cancer cells, by Western blotting and reverse transcription- polymerase chain reaction, and by assays for cell viability, migration, and invasion. Results: Src was activated in four of five cell lines tested and the level corresponded with the invasive potential and the histologic subtype. Clinically relevant, submicromolar concentrations of AZD0530 blocked Src and focal adhesion kinase, resulting in significant inhibition of cell migration and Matrigel invasion. Reactivation of STAT3 and up-regulation of JAK indicated a potential mechanism of resistance. AZD0530 gave a potent and sustained blockage of AKT and enhanced the sensitivity to irradiation. Conclusions: The results indicated that AZD0530, aside from being a potent inhibitor of tumor cell invasion which could translate to inhibition of disease progression in the clinic, may also lower resistance of lung cancer cells to pro-apoptotic signals. copy; 2009 by the International Association for the Study of Lung Cancer.",
keywords = "Invasion, Lung cancer, Metastasis, Protein kinase B, Signal transducer and activator of transcription, Src",
author = "Purnell, {Phillip R.} and Mack, {Philip C.} and Tepper, {Clifford G.} and Evans, {Christopher P.} and Green, {Tim P.} and Gumerlock, {Paul H.} and Lara, {Primo N.} and Gandara, {David R.} and Kung, {Hsing Jien} and Oliver Gautschi",
year = "2009",
month = "1",
day = "1",
doi = "10.1097/JTO.0b013e31819c78fb",
language = "English",
volume = "4",
pages = "448--454",
journal = "Journal of Thoracic Oncology",
issn = "1556-0864",
publisher = "International Association for the Study of Lung Cancer",
number = "4",

}

TY - JOUR

T1 - The src inhibitor AZD0530 blocks invasion and may act as a radiosensitizer in lung cancer cells

AU - Purnell, Phillip R.

AU - Mack, Philip C.

AU - Tepper, Clifford G.

AU - Evans, Christopher P.

AU - Green, Tim P.

AU - Gumerlock, Paul H.

AU - Lara, Primo N.

AU - Gandara, David R.

AU - Kung, Hsing Jien

AU - Gautschi, Oliver

PY - 2009/1/1

Y1 - 2009/1/1

N2 - With the emergence of Src inhibitors in clinical trials, improved knowledge of the molecular responses of cancer cells to these agents is warranted. This will facilitate the development of tests to identify patients who may benefit from these agents, allow drug activity to be monitored and rationalize the combination of these agents with other treatment modalities. Methods: This study evaluated the molecular and functional effects of Src inhibitor AZD0530 in human lung cancer cells, by Western blotting and reverse transcription- polymerase chain reaction, and by assays for cell viability, migration, and invasion. Results: Src was activated in four of five cell lines tested and the level corresponded with the invasive potential and the histologic subtype. Clinically relevant, submicromolar concentrations of AZD0530 blocked Src and focal adhesion kinase, resulting in significant inhibition of cell migration and Matrigel invasion. Reactivation of STAT3 and up-regulation of JAK indicated a potential mechanism of resistance. AZD0530 gave a potent and sustained blockage of AKT and enhanced the sensitivity to irradiation. Conclusions: The results indicated that AZD0530, aside from being a potent inhibitor of tumor cell invasion which could translate to inhibition of disease progression in the clinic, may also lower resistance of lung cancer cells to pro-apoptotic signals. copy; 2009 by the International Association for the Study of Lung Cancer.

AB - With the emergence of Src inhibitors in clinical trials, improved knowledge of the molecular responses of cancer cells to these agents is warranted. This will facilitate the development of tests to identify patients who may benefit from these agents, allow drug activity to be monitored and rationalize the combination of these agents with other treatment modalities. Methods: This study evaluated the molecular and functional effects of Src inhibitor AZD0530 in human lung cancer cells, by Western blotting and reverse transcription- polymerase chain reaction, and by assays for cell viability, migration, and invasion. Results: Src was activated in four of five cell lines tested and the level corresponded with the invasive potential and the histologic subtype. Clinically relevant, submicromolar concentrations of AZD0530 blocked Src and focal adhesion kinase, resulting in significant inhibition of cell migration and Matrigel invasion. Reactivation of STAT3 and up-regulation of JAK indicated a potential mechanism of resistance. AZD0530 gave a potent and sustained blockage of AKT and enhanced the sensitivity to irradiation. Conclusions: The results indicated that AZD0530, aside from being a potent inhibitor of tumor cell invasion which could translate to inhibition of disease progression in the clinic, may also lower resistance of lung cancer cells to pro-apoptotic signals. copy; 2009 by the International Association for the Study of Lung Cancer.

KW - Invasion

KW - Lung cancer

KW - Metastasis

KW - Protein kinase B

KW - Signal transducer and activator of transcription

KW - Src

UR - http://www.scopus.com/inward/record.url?scp=67649396221&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=67649396221&partnerID=8YFLogxK

U2 - 10.1097/JTO.0b013e31819c78fb

DO - 10.1097/JTO.0b013e31819c78fb

M3 - Article

VL - 4

SP - 448

EP - 454

JO - Journal of Thoracic Oncology

JF - Journal of Thoracic Oncology

SN - 1556-0864

IS - 4

ER -