||Receptor tyrosine kinases (RTKs) and their pleiotropic effectors play key roles in metastasis. Met and Ron are RTKs that have been shown to contribute to tumor growth and metastasis in both animal models and in patients. Recently, an alternative Ron isoform known as "short-form" Ron (sfRon) was associated with aggressive phenotype of breast cancer. The expression of this alternative Ron isoform yields constitutively active protein, and promotes tumor growth and spontaneous metastasis to distant organs. We observed that sfRon strongly signals through the PI3K pathway and that interaction between sfRon and PI3K is required for sf Ron function. The PI3K signaling cascade regulates many cellular functions that are mainly associated with cell proliferation, survival, and migration. Blocking the interaction between sfRon and PI3K, or directly blocking PI3K activity, thoroughly abrogates the ability of sfRon to confer aggressive tumor behavior in vitro. In our study we utilized the inhibitor drugs NVP-BEZ235, NVP-BKM120, and ASLAN002. For in vivo studies, we used highly tumorigenic and invasive MCF7 breast cancer cells. Our cell line over-expresses sfRon and is characterized by high levels of active PI3K. We have shown before that sfRon overexpression triggers activation of PI3K signaling, which is necessary for sfRon aggressive behavior. Our goal was to test whether inhibition of PI3K pathway, which signals downstream from sfRon, will have any effect on this aggressive tumor growth in vivo. Our data shows that PI3K pathway inhibitors are very well tolerated by mice and are excellent in the inhibition of tumor growth driven by sfRon, especially NVP-BKM120. These compounds hold great promise in the treatment of breast cancer overexpressing sfRon with strongly activated PI3K.