Cooperative Roles of Class IA PI3K Isoforms in Translocation-Related Sarcoma Cell Survival and Proliferation

Among class I phosphatidylinositol 3-kinase (PI3K) isoforms, the isoform that predominantly regulates proliferation and survival in cancer dependent on PI3K signaling differs according to the genetic background and lineage of origin. We previously reported that translocation-related sarcomas (TRS) such as synovial sarcoma and Ewing sarcoma are highly susceptible to pan-class I PI3K inhibitors, but the dominant isoform remains unclear. To address this issue, we examined the roles of each PI3K isoform in TRS cells. Neither class I PI3K isoforms nor PI3K-related genes in sarcoma cell lines, including TRS, exhibited common mutations. Selective inhibition of PI3Kα moderately suppressed Akt/mTOR signaling, leading to growth inhibition and apoptosis, whereas inhibiting PI3Kβ or PI3Kδ alone had no effect. Interestingly, inhibition of PI3Kα together with PI3Kβ and/or PI3Kδ significantly enhanced apoptosis induction versus PI3Kα inhibition alone. In contrast, carcinoma cell lines did not undergo apoptosis upon PI3K inhibition, except for PIK3CA-mutated cell lines. In those cell lines, PI3Kα inhibition alone significantly induced apoptosis with no enhancement in simultaneous inhibition of PI3K isoforms. Mechanistically, whereas PI3Kα primarily mediated Akt/mTOR signaling in TRS cells, PI3Kβ and PI3Kδ compensated for Akt/mTOR signaling when PI3Kα was inhibited. Simultaneous inhibition of PI3Kα, PI3Kβ, and PI3Kδ was more potent than individual inhibition against TRS cells in a mouse xenograft model. These findings suggest that PI3Kα is the dominant isoform, whereas PI3Kβ and PI3Kδ cooperate with PI3Kα in cell survival, which seems to be a characteristic feature of TRS cells. Thus, triple-isoform inhibition might represent an effective therapy for TRSs. SIGNIFICANCE: PI3Kα is the dominant isoform regulating cell survival, whereas PI3Kβ and PI3Kδ complement PI3Kα, suggesting that coinhibition of class IA PI3K isoforms could be a potential therapeutic strategy for TRSs.