Abstract Background: Dysregulation of the PI3K-AKT signaling pathway has been implicated as a key driver in cancer initiation and progression. AKT is a serine/threonine kinase and a critical component mediating the PI3K-AKT signaling axis. Although AKT inhibitors have been extensively studied, clinical outcome has not been impressive. Interestingly, it has been shown that PI3K/AKT pathway has been involved in resistance to conventional chemotherapy, and inhibition of AKT enhances targeted therapy and sensitizes radiation therapy. ARQ 092 is a potent and selective pan-AKT inhibitor and currently in early clinical studies. In this study, we assessed combined effect of ARQ 092 with a chemotherapeutic agent, anti-MEK and andi-HER2 agents, and ARQ 087, a pan-FGFR experimental inhibitor in vitro and in vivo. Methods: In vitro ARQ 092 and ARQ 087 combination studies were performed based on the Chou-Talalay method and combinatorial indices were calculated. In vivo, ARQ 092 at doses of 20-120mg/Kg was tested in combination with paclitaxel, lapatinib, trastuzumab, trametinib, and ARQ 087. Xenografts used were endometrial (AN3CA) and breast (HCC1954, KPL-4, ZR-75-1) tumors, two patient-derived (PDX) models of endometrial (with PIK3CAH1047R and R93W+D350G mutations) and in one vemurafenib-resistant melanoma PDX (with BRAFV600E and PIK3CA H1047R mutations). With the AN3CA model, pathway analysis was performed by Western blot, and blood/tumor pharmacokinetic was analyzed. Results: Among all cell lines tested with the combination of ARQ 092 and ARQ 087, the highest rate of synergism was found in endometrial and ovarian cancers, respectively in 44% (4/9, 3 bearing both PIK3CA/PIK3R1 and FGFR2 mutations) and 38% (3/8, all with PIK3CA/R1 mutations). In six in vivo mouse xenograft models, ARQ 092 enhanced efficacy of paclitaxel, lapatinib, trastuzumab, and ARQ 087 by reducing tumor growth as much as 85%, 73%, 91%, 86% respectively, while single agent comparators reduced tumors by 38%, 0%, 30%, and 32% respectively. In endometrial PDX models, the combination of ARQ 092 with trametinib and ARQ 087 enhanced anti-tumor activity of each drug alone, reducing tumor growth by 67% and 71%, respectively compared to single-agent tumor reductions by 43% and 2%. When combined with trametinib tumor growth was reduced by 73% in a vemurafenib-resistant melanoma PDX model, while trametinib alone only reduced tumor growth by 26%. When ARQ 092 was combined with ARQ 087, pathway analysis showed 76% pAKT inhibition and 86% pFGFR inhibition, while single agent ARQ 087 inhibited pFGFR by 43%. PK analysis showed ARQ 092 accumulates up to 21 μM in tumor vs 0.6 μM in plasma (35 fold). ARQ 087 also accumulates in tumor and was elevated when combined with ARQ 092: 1.1 μM in plasma and 20 μM in tumor (20 fold) as single agent vs 2.7 μM in plasma and 110 μM in tumor (41 fold) when combined with ARQ 092. Conclusions: ARQ 092 enhances in vivo anti-tumor activity of paclitaxel, lapatinib, trastuzumab, trametinib. ARQ 092 is synergistic, in vitro and in vivo, with ARQ 087, with significant PI3K/AKT and FGFR pathway inhibition. Citation Format: Yi Yu, Justin Meade, Michael J. Wick, Hall Terence, Sudhi Eathiraj, Brian Schwartz, Giovanni Abbadessa. ARQ 092 enhances the efficacy of paclitaxel, lapatinib, trastuzumab, trametinib, and ARQ 087 both in cancer cell lines and mouse xenograft cancer models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B185.