Synergistic anti-tumor effect of combined inhibition of EGFR and JAK/STAT3 pathways in human ovarian cancer.
BACKGROUND
The EGFR signaling pathway is frequently activated in human ovarian cancer and associated with poor prognosis. However, inhibition of EGFR signaling in patients with recurrent ovarian cancer has been disappointing. It remains to be addressed whether ovarian cancer patients could benefit from targeting EGFR signaling. Here we investigated the mechanisms underlying the resistance to EGFR inhibition in ovarian cancer and developed a strategy to overcome it.


RESULTS
We found that treatment of human ovarian cancer cells with an EGFR inhibitor, gefitinib, resulted in increased STAT3 phosphorylation in a dose- and time-dependent manner. Inhibiting STAT3 activation with a small molecule inhibitor of JAK, an upstream kinase that phosphorylates and activates STAT3, synergistically increased the anti-tumor activity of gefitinib in vitro. Similar results were obtained when STAT3 or JAK1 expression was knocked down. In contrast, inhibiting other signaling pathways, such as AKT/mTOR, MEK or SRC, was relatively less effective. The combined treatment resulted in simultaneous attenuation of multiple survival pathways and increased inhibition of ERK pathway. In addition, the dual inhibition showed a stronger suppression of xenograft tumor growth than either single inhibition.


CONCLUSIONS
Our findings demonstrate that feedback activation of STAT3 pathway might contribute to the resistance to EGFR inhibition. Combined blockade of both pathways appears to be more effective against human ovarian cancer than inhibition of each pathway alone both in vitro and in vivo. This study may provide a strategy to improve clinical benefit of targeting EGFR pathway in ovarian cancer patients.
Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 East Duarte Rd., Duarte, CA, 91010, USA. wwen@coh.org.|Department of Surgery, Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 East Duarte Rd., Duarte, CA, 91010, USA. wwen@coh.org.
Wei
W
Wen
Department of Comparative Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 East Duarte Rd., Duarte, CA, 91010, USA. jwu@coh.org.
Jun
J
Wu
Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 East Duarte Rd., Duarte, CA, 91010, USA. lucyxliu1212@gmail.com.
Lucy
L
Liu
Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 East Duarte Rd., Duarte, CA, 91010, USA. tyfxh@163.com.
Yan
Y
Tian
Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 East Duarte Rd., Duarte, CA, 91010, USA. rbuettner@coh.org.
Ralf
R
Buettner
Department of Comparative Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 East Duarte Rd., Duarte, CA, 91010, USA. mhsieh@coh.org.
Meng-Yin
MY
Hsieh
Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 East Duarte Rd., Duarte, CA, 91010, USA. dhorne@coh.org.
David
D
Horne
Department of Surgery, Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 East Duarte Rd., Duarte, CA, 91010, USA. tdellinger@coh.org.
Thanh H
TH
Dellinger
Department of Surgery, Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 East Duarte Rd., Duarte, CA, 91010, USA. ehan@coh.org.
Ernest S
ES
Han
Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 East Duarte Rd., Duarte, CA, 91010, USA. rjove@vgtifl.org.|Vaccine & Gene Therapy Institute of Florida, 9801 SW Discovery Way, Port St. Lucie, 34987, Florida, USA. rjove@vgtifl.org.
Richard
R
Jove
Department of Surgery, Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 East Duarte Rd., Duarte, CA, 91010, USA. jyim@coh.org.
John H
JH
Yim
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D000077156:Gefitinib; D055785:Gene Knockdown Techniques; D006801:Humans; D053612:Janus Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D054852:Small Molecule Libraries / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D050796:STAT3 Transcription Factor; D054852:Small Molecule Libraries; D066246:ErbB Receptors; D053612:Janus Kinases; D000077156:Gefitinib