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Metastasis is a big issue to cancer therapy and is the major cause of therapeutic failure and cancer death. Therefore, inhibiting cancer metastasis is a key challenge in cancer treatment. Ovarian cancer is the most deadly cancer among women and combination treatment strategy is usually used to fight against this disease not only to reduce the toxicity and side effects, but also to enhance the anticancer effect. (R)(S)(S)-BF65 is a hemiasterlin derivative and potent anti-tubulin agent with IC50 values in the low nanomolar range against various cancer cells. Previous studies indicated that (R)(S)(S)-BF65 in combination with an allosteric Akt inhibitor MK-2206 synergistically inhibited the growth of SKOV3 human ovarian cancer cells. Using the MTT assay, we demonstrated that (R)(S)(S)-BF65 could also enhanced the growth inhibitory effect of NVP-BEZ235, a PI3K/mTOR dual inhibitor in SKOV3 cells. The IC50 was 11.6 μM for NVP-BEZ235 and 20.6 nM for (R)(S)(S)-BF65 after 48 h-treatment. With a molar ratio of 1:1000 or 1:500, the combination of (R)(S)(S)-BF65 and NVP-BEZ235 displayed an additive to mild synergistic cytotoxic effect with CI50 values of 0.96 and 0.91, respectively. Interestingly, the combination of (R)(S)(S)-BF65 and NVP-BEZ235, at concentrations much lower than those required for growth inhibition, significantly inhibited cell migration and invasion as demonstrated by wound healing migration, transwell migration and invasion assays. The combinatorial effect was much more effective than single treatments. Epithelial-mesenchymal transition (EMT) plays an important role in cancer metastasis. It has been reported that activation of the PI3K/Akt pathway leads to phosphorylation and inactivation of GSK3β, which may in turn induce EMT. Western blot analysis of EMT markers revealed that NVP-BEZ235 downregulated mesenchymal markers β-catenin and Slug, and upregulated the epithelial marker, E-cadherin. (R)(S)(S)-BF65 also downregulated mesenchymal markers β-catenin and Snail, but had no effect on E-cadherin. The combination of both led to downregulation of more mesenchymal markers including β-catenin, Slug, Snail and ZEB1, and upregulation of E-cadherin, which may at least in part explain why the combination was more effective than single treatments to suppress cell migration and invasion. Taken together, the combination of (R)(S)(S)-BF65 and NVP-BEZ235 may be a promising strategy to inhibit ovarian cancer growth and metastasis. Citation Format: Po-Chia Su, Tzu-En Huang, Lih-Ching Hsu. Combination of hemiasterlin derivative (R)(S)(S)-BF65 and PI3K/mTOR dual inhibitor NVP-BEZ235 as a new strategy to inhibit ovarian cancer growth and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2941.