Spleen tyrosine kinase activity regulates epidermal growth factor receptor signaling pathway in ovarian cancerResearch in context
Yu Yu,
Yohan Suryo Rahmanto,
Yao-An Shen,
Laura Ardighieri,
Ben Davidson,
Stephanie Gaillard,
Ayse Ayhan,
Xu Shi,
Jianhua Xuan,
Tian-Li Wang,
Ie-Ming Shih
Affiliations
Yu Yu
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231, United States of America; Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21205, United States of America; Corresponding authors.
Yohan Suryo Rahmanto
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231, United States of America; Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21205, United States of America
Yao-An Shen
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231, United States of America; Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21205, United States of America
Laura Ardighieri
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21205, United States of America
Ben Davidson
Department of Pathology, Oslo University Hospital and Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Norwegian Radium Hospital, 0310 Oslo, Norway
Stephanie Gaillard
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231, United States of America
Ayse Ayhan
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21205, United States of America; Department of Pathology, Seirei Mikatahara Hospital, Hamamatsu and Hiroshima Universities Schools of Medicine, Hamamatsu 431-3192, Japan
Xu Shi
Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Arlington, VA 22203, United States of America
Jianhua Xuan
Bradley Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Arlington, VA 22203, United States of America
Tian-Li Wang
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231, United States of America; Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21205, United States of America; Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD 21287, United States of America; Corresponding authors.
Ie-Ming Shih
Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD 21231, United States of America; Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD 21287, United States of America; Corresponding authors.
Background: Spleen tyrosine kinase (SYK) is frequently upregulated in recurrent ovarian carcinomas, for which effective therapy is urgently needed. SYK phosphorylates several substrates, but their translational implications remain unclear. Here, we show that SYK interacts with EGFR and ERBB2, and directly enhances their phosphorylation. Methods: We used immunohistochemistry and immunoblotting to assess SYK and EGFR phosphorylation in ovarian serous carcinomas. Association with survival was determined by Kaplan-Meier analysis and the log-rank test. To study its role in EGFR signaling, SYK activity was modulated using a small molecule inhibitor, a syngeneic knockout, and an active kinase inducible system. We applied RNA-seq and phosphoproteomic mass spectrometry to investigate the SYK-regulated EGF-induced transcriptome and downstream substrates. Findings: Induced expression of constitutively active SYK130E reduced cellular response to EGFR/ERBB2 inhibitor, lapatinib. Expression of EGFRWT, but not SYK non-phosphorylatable EGFR3F mutant, resulted in paclitaxel resistance, a phenotype characteristic to SYK active ovarian cancers. In tumor xenografts, SYK inhibitor reduces phosphorylation of EGFR substrates. Compared to SYKWT cells, SYKKO cells have an attenuated EGFR/ERBB2-transcriptional activity and responsiveness to EGF-induced transcription. In ovarian cancer tissues, pSYK (Y525/526) levels showed a positive correlation with pEGFR (Y1187). Intense immunoreactivity of pSYK (Y525/526) correlated with poor overall survival in ovarian cancer patients. Interpretation: These findings indicate that SYK activity positively modulates the EGFR pathway, providing a biological foundation for co-targeting SYK and EGFR. Fund: Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, NIH/NCI, Ovarian Cancer Research Foundation Alliance, HERA Women's Cancer Foundation and Roseman Foundation. Funders had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript and eventually in the decision to submit the manuscript.
