The PI3K/Akt signaling pathway, Notch, and other oncogenes cooperate in the induction
of aggressive cancers. Elucidating how the PI3K/Akt pathway facilitates tumorigenesis
by other oncogenes may offer opportunities to develop drugs with fewer side effects
than those currently available. Here, using an unbiased in vivo chemical genetic screen
in Drosophila, we identified compounds that inhibit the activity of proinflammatory
enzymes nitric oxide synthase (NOS) and lipoxygenase (LOX) as selective suppressors
of Notch-PI3K/Akt cooperative oncogenesis. Tumor silencing of NOS and LOX signaling
mirrored the antitumor effect of the hit compounds, demonstrating their participation
in Notch-PI3K/Akt- induced tumorigenesis. Oncogenic PI3K/Akt signaling triggered inflammation
and immunosuppression via aberrant NOS expression. Accordingly, activated Notch tumorigenesis
was fueled by hampering the immune response or by NOS overexpression to mimic a protumorigenic
environment. Our lead compound, the LOX inhibitor BW B70C, also selectively killed
human leukemic cells by dampening the NOTCH1-PI3K/AKT-eNOS axis.
