Eph
proteins have emerged as critical drivers affecting
tumor growth and progression in human
malignancies. Our The
Cancer Genome Atlas (TCGA) data analysis showed that EphB3, a
receptor tyrosine kinase, is frequently coamplified with PIK3CA in
head and neck squamous cell carcinoma (
HNSCC). We therefore hypothesized that EphB3 amplification plays a protumorigenic role in
HNSCC and that EphB3 and PIK3CA are cooperating oncogenes that contribute toward its pathogenesis. This hypothesis was not experimentally supported, because EphB3 knockdown failed to alter
HNSCC tumor cell growth in vitro or in vivo with an orthotopic model. However, responsiveness of EphB3 knockdown
tumors to the PI3K inhibitor,
BKM120, was significantly decreased in terms of both
tumor growth delay and survival. This is correlated with an increase in prosurvival
proteins, S6 and BcL-XL, in the EphB3
shRNA tumors treated with
BKM120 compared with controls. We further observed that EphB3 knockdown resulted in increased migration in vitro and increased EMT gene signature in vivo To explain these results, we examined EphB3 phosphorylation levels in
HNSCC at baseline. Although total EphB3 levels were high, we found low phospho-EphB3 levels in HNSCCs. Forced EphB3 phosphorylation with an ephrin-B2-Fc fusion
protein resulted in decreased
HNSCC migration and cell growth, and enhanced response to
BKM120 in vitro These data collectively indicate that progression of
HNSCC selects for low/inhibited EphB3 activity to enhance their survival and migratory abilities and decrease response to PI3K signaling. Therefore, strategies focused on activating EphB3 might be helpful to inhibit
tumor growth and enhance sensitivity to PI3K inhibitors in
HNSCC. Mol
Cancer Ther; 17(9); 2049-59. ©2018 AACR.