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

Abstract

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 (GAB2^High). 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 GAB2^High HGSOC progression. Analysis of gene expression data reveals that primary GAB2^High 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 GAB2^High 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 GAB2^High 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 GAB2^High ovarian cancer cells, and combinatorial SHP2 and PI3K inhibition may be a promising therapeutic approach for such cancer.

Keywords: GAB2; High-grade serous ovarian cancer; PI3K; SHP2.