Synergistic effects of SHP2 and PI3K pathway inhibitors in GAB2-overexpressing ovarian cancer

American Journal of Cancer Research

Nathaniel R Jensen¹  Meixiang Yang²  Dongjun Chung³  Bowen Sun⁴ 

[1]Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA

[2]Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC 29425, USA

[3]Ralph H. Johnson VAMC, Department of Veterans Affairs, Charleston, SC 29401, USA

[4]The First Affiliate Hospital, Biomedical Translational Research Institute, Guangdong Province Key Laboratory of Molecular Immunology and Antibody Engineering, Jinan University, Guangzhou 510632, China

关键词: High-grade serous ovarian cancer;    GAB2;    PI3K;    SHP2;   

DOI  :  

学科分类：肿瘤学

来源: e-Century Publishing Corporation

【 摘 要 】

The scaffold/adaptor growth factor receptor bound 2 (GRB2)-associated binding protein 2 (GAB2) is frequently amplified and/or overexpressed in primary high-grade serous ovarian cancers (HGSOCs). Here we investigate a novel treatment strategy by targeting SHP2 and PI3K signaling in HGSOCs with GAB2 amplification/overexpression (GAB2High). The expression of GAB2 was analyzed in primary HGSOCs and ovarian cancer cell lines. In vitro and in vivo assays were performed to demonstrate the effect of SHP2 and PI3K-mediated GAB2High HGSOC progression. Analysis of gene expression data reveals that primary GAB2High HGSOCs are associated with increased ERBB, RAS, and MAPK activity signatures. Inhibition of SHP2 by an allosteric inhibitor SHP099 selectively inhibits ERK1/2 activity, proliferation, and survival of GAB2High ovarian cancer cell lines. Treatment with SHP099 has a synergistic effect with BKM120, a pan-class I PI3K inhibitor, at suppressing proliferation and survival of GAB2High ovarian cancer cells in vitro and in vivo by more effectively activating both BIM and BAD and inhibiting c-MYC compared with individual inhibitor. Our findings identify an important role of SHP2 in promoting proliferation and survival of GAB2High ovarian cancer cells, and combinatorial SHP2 and PI3K inhibition may be a promising therapeutic approach for such cancer.

【 授权许可】

CC BY-NC