The Src inhibitor AZD0530 blocks invasion and may act as a radiosensitizer in lung cancer cells.
BACKGROUND
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.
Purnell
Phillip R
PR
University of California Davis Cancer Center, Sacramento, California, USA.
Mack
Philip C
PC
Tepper
Clifford G
CG
Evans
Christopher P
CP
Green
Tim P
TP
Gumerlock
Paul H
PH
Lara
Primo N
PN
Gandara
David R
DR
Kung
Hsing-Jien
HJ
Gautschi
Oliver
O
D052117:Benzodioxoles / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000502:physiology; D006801:Humans; D053616:Janus Kinase 3 / Q000235:genetics / Q000502:physiology; D008175:Lung Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D009025:Morpholines / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000502:physiology; D011799:Quinazolines / Q000494:pharmacology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000032:analysis / Q000502:physiology; D015398:Signal Transduction; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
D052117:Benzodioxoles; D002867:Chromones; D009025:Morpholines; D011799:Quinazolines; D011838:Radiation-Sensitizing Agents; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C515233:saracatinib; D019869:Phosphatidylinositol 3-Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases; C507933:JAK3 protein, human; D053616:Janus Kinase 3; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt