Ewing Sarcoma is an aggressive
malignancy of bone and soft tissue affecting children and young adults.
Ewing Sarcoma is driven by EWS/Ets fusion
oncoproteins, which cause widespread alterations in gene expression in the cell. Dysregulation of
receptor tyrosine kinase signaling, particularly involving IGF-1R, also plays an important role in
Ewing Sarcoma pathogenesis. However, the basis of this dysregulation, including the relative contribution of EWS/Ets-dependent and independent mechanisms, is not well understood. In the present study, we identify variable expression of two modifiers of PI3K signaling activity, PIK3R3 and PTEN, in
Ewing Sarcoma, and examine the consequences of this on PI3K pathway regulation and oncogenic phenotypes. Our findings indicate that PIK3R3 plays a growth-promotional role in
Ewing Sarcoma, but suggest that this role is not strictly dependent on regulation of PI3K pathway activity. We further show that expression of PTEN, a well-established, potent
tumor suppressor, is lost in a subset of Ewing
Sarcomas, and that this loss strongly correlates with high baseline PI3K pathway activity in cell lines. In support of functional importance of PTEN loss in
Ewing Sarcoma, we show that re-introduction of PTEN into two different PTEN-negative
Ewing Sarcoma cell lines results in downregulation of PI3K pathway activity, and sensitization to the IGF-1R small molecule inhibitor
OSI-906. Our findings also suggest that PTEN levels may contribute to sensitivity of
Ewing Sarcoma cells to the microtubule inhibitor
vincristine, a relevant chemotherapeutic agent in this
cancer. Our studies thus identify PIK3R3 and PTEN as modifiers of oncogenic phenotypes in
Ewing Sarcoma, with potential clinical implications.