Lucitanib (S 80881, E-3810, CO-3810) is a potent inhibitor of the fibroblast growth factor receptors 1-3 (FGFR1-3), vascular endothelial growth factor receptors 1-3 (VEGFR1-3) and platelet-derived growth factor receptors alpha and beta (PDGFRα/β). A Phase 1/2 clinical study (Soria et al., 2014) of lucitanib showed a RECIST response rate of 50% in breast cancer patients with FGF-aberrant (FGFR1 and/or FGF3/4/19 gene amplified) tumors. Here we explored potential drug partners that can be used in combination with lucitanib to increase cell cytotoxicity. Five FGF-dependent breast carcinoma cell lines were evaluated - MFM-223 (human TNBC, FGFR1 / FGFR2 amplified, PIK3CA H1047R); HCC38 (human TNBC, FGFR1 high expression, PIK3CA W386L); CAL-120 (human TNBC, FGFR1 / FRS2 amplified, PIK3CA wild-type); EFM-19 (human ER+ BC, FGFR2 K659E, PIK3CA H1047L); and 4T1 (mouse TNBC, FGFR2 high expression, PIK3CA wild-type). Single agent and lucitanib drug-drug combinations were evaluated in 2D monolayer and/or 3D spheroid culture using a broad (MFM-223; n = 350 compounds) or a more focused compound library (cell lines CAL-120, EFM-19 and MFM-223; n = 70 compounds approved or in clinical trials). Drug combinations were evaluated at a concentration range of 0.06-5000 nM and co-cultured with 0.2 μM lucitanib in a 72-hour cell viability assay. Combination efficacy was determined by comparing cell viability with and without lucitanib either by direct comparison of raw RLU or by fold change in calculated GI50. Several compounds were identified that enhanced cell killing when combined with lucitanib, including HDAC inhibitors (vorinostat, entinostat and belinostat), PI3K/Akt/mTOR pathway inhibitors (GDC-0941, GDC-0980 and BLY719), EGFR/HER2 inhibitors (afatinib and lapatinib), and CDK inhibitors (AT7519 and flavopiridol). These combinations were examined for efficacy across all five cell lines, and combination indexes (CI) were calculated to determine synergy. The PI3K/Akt/mTOR and lucitanib combination demonstrated consistent synergy across all cell lines independent of PIK3CA mutation status. For example, the PI3K inhibitor GDC-0941 showed a CI range of 0.04-0.58 at the GI50 (CI < 1 synergistic). Greater cell killing by combined PI3K/AKT and FGFR inhibition was also shown to correlate with increased inhibition of p-AKT by immunoblotting. In conclusion, the activity of lucitanib in FGFR-driven breast carcinoma cells is augmented by the addition of PI3K/AKT/mTOR inhibitors, and dual targeting of AKT and FGFR signaling may enhance the clinical activity of these agents.
Citation Format: Minh Nguyen, Liliane Robillard, Andrew D. Simmons, Henry J. Haringsma, Thomas C. Harding. PI3K/AKT/mTOR inhibitors enhance the anti-tumor activity of the FGFR, VEGFR and PDGFR inhibitor lucitanib in FGF-dependent breast 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 C199.