Abstract B114: Combination of BGJ398 with either a pan-PI3K inhibitor or a specific PIK3CA inhibitor shows synergy in FGFR2 mutant endometrial cancer cell lines

Abstract

Abstract Background: Our lab has identified FGFR2 mutations in 12% of over 1500 endometrioid endometrial cancers (ECs) analyzed. The majority of these tumors harbor genetic aberrations in the PI3K/AKT pathway resulting in constitutive activation. In other tissue types, PTEN loss has been shown to provide resistance to specific PIK3CA inhibition. We have previously reported that FGFR inhibition with PD173074 induced cell death despite loss of PTEN. We hypothesize that dual inhibition of FGFR2 and the PI3K pathway will lead to increased cell death and more effective tumor growth inhibition. Materials and Methods: Two FGFR2 mutant EC cell lines were treated with BGJ398 (pan FGFR inhibitor) alone or in combination with either a pan-PI3K inhibitor (GDC0941) or a specific PI3KA inhibitor (BYL719). Synergy was assessed using the fixed ratio method proposed by Chou and Talalay. Cell death was determined by Annexin V staining and colony formation assays using low clinically relevant drug concentrations. Downstream signaling pathways were analyzed by Western blot analysis and BGJ398 in combination with either GDC0941 or BYL719 was assessed in vivo. Results: Synergy was observed between BGJ398 and either the pan-PI3K inhibitor (GDC0941), or the specific PI3KA inhibitor (BYL719). Regression of tumor xenografts was observed in mice treated with BGJ398 and GDC0941 as well as BGJ398 and BYL719, despite PTEN inactivation. Conclusions: Dual targeting of the FGFR and PI3K pathways is more effective than targeting either of them alone. PTEN loss does not provide resistance to PIK3CA inhibition in our EC models suggesting context dependent differences in PI3K signaling. Citation Format: Pamela M. Pollock, Xinyan Geng, Vanessa F. Bonazzi, Clare Mahon, Sally Stephenson, Leisl Packer. Combination of BGJ398 with either a pan-PI3K inhibitor or a specific PIK3CA inhibitor shows synergy in FGFR2 mutant endometrial cancer cell lines. [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 B114.