Synergistic anti-tumor effect of combined inhibition of EGFR and JAK/STAT3 pathways in human ovarian cancer

Molecular Cancer

Research

Meng-Yin Hsieh¹  Jun Wu¹  David Horne²  Ralf Buettner²  Lucy Liu²  Yan Tian²  Wei Wen³  Richard Jove⁴  John H Yim⁵  Ernest S Han⁵  Thanh H Dellinger⁵ 

[1] Department of Comparative Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 East Duarte Rd., 91010, Duarte, CA, USA;Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 East Duarte Rd., 91010, Duarte, CA, USA;Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 East Duarte Rd., 91010, Duarte, CA, USA;Department of Surgery, Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 East Duarte Rd., 91010, Duarte, CA, USA;Department of Molecular Medicine, Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 East Duarte Rd., 91010, Duarte, CA, USA;Vaccine & Gene Therapy Institute of Florida, 9801 SW Discovery Way, 34987, Port St. Lucie, Florida, USA;Department of Surgery, Beckman Research Institute, City of Hope Comprehensive Cancer Center, 1500 East Duarte Rd., 91010, Duarte, CA, USA;

关键词: Ovarian cancer;    EGFR resistance;    JAK/STAT3;    feedback;    combination;    synergy;   

DOI  :  10.1186/s12943-015-0366-5

 received in 2014-12-12, accepted in 2015-04-10,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundThe 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.ResultsWe 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.ConclusionsOur 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.

【 授权许可】

CC BY   
© Wen et al.; licensee BioMed Central. 2015