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.
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 mumol/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.
Division of Hematology/Oncology, Department of Medicine, Case Western Reserve University and University Hospitals of Cleveland and CASE Comprehensive Cancer Center, Cleveland, Ohio 44106, USA. afshin.dowlati@case.edu
Afshin
A
Dowlati
Amy
A
Kluge
David
D
Nethery
Balazs
B
Halmos
Jeffrey A
JA
Kern
D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003124:Colorimetry; D004357:Drug Synergism; D005434:Flow Cytometry; D006801:Humans; D007202:Indicators and Reagents; D000077341:Lapatinib; D009154:Mutation / Q000235:genetics / Q000502:physiology; D051058:Oncogene Protein v-akt / Q000037:antagonists & inhibitors; D010880:Piperidines / Q000494:pharmacology*; D054876:Prenylation / Q000187:drug effects*; D011725:Pyridines / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D003986:Dibenzocycloheptenes
D007202:Indicators and Reagents; D000077341:Lapatinib; D051058:Oncogene Protein v-akt; D010880:Piperidines; D011725:Pyridines; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D050796:STAT3 Transcription Factor; C508053:ERBB2 protein, human; C115354:lonafarnib; D003986:Dibenzocycloheptenes