Abstract B259: Combined targeting of FGFR2 and mTOR by AP24534 and ridaforolimus results in synergistic antitumor activity in FGFR2-driven endometrial cancer models
Authors: Gozgit Joseph M. , Squillace Rachel M. , Wong Matthew J. , Miller David , Wardwell Scott , Berk Lori , Moran Lauren , Mohemmad Qurish , Narasimhan Narayana I. , Shakespeare William C. , Wang Frank , Clackson Tim , Rivera Victor M. 
Published: June 2012

Purpose: Members of the fibroblast growth factor receptor family (FGFR1–4) are dysregulated in a number of cancer types and play key roles in tumorigenesis. In particular, activating mutations in FGFR2 have been identified in 16% of endometrial tumors. Such mutations have been shown to occur frequently alongside PTEN mutations, resulting in simultaneous activation of the MAPK and mTOR pathways. Here we evaluated the activity of the multi-targeted kinase inhibitor AP24534, which is currently in phase 1 clinical testing, against FGFR2 and other FGFR family members, and investigated the ability of AP24534, plus the mTOR inhibitor ridaforolimus, to inhibit growth in endometrial cancer models.

Results: We first evaluated the ability of AP24534 to block FGFR signaling and inhibit growth of FGFR-driven cell lines. AP24534 potently blocked signaling of all 4 FGFRs with IC50s between 4–65 nM. This correlated with anti-proliferative activity observed across a panel of cell lines, with GI50s between 10–275 nM. The anti-proliferative activity of AP24534 compared favorably to that of other agents reported to have anti-FGFR activity (i.e. AZD2171, CHIR-258, BIBF 1120 and BMS-540215). In endometrial cancer models AP24534 potently inhibited growth of 2 lines with an activating FGFR2 mutation (N549K), that differ in PTEN status, AN3CA (PTEN−/−) and MFE-296 (PTEN+/+), with GI50s of 30 and 90 nM, respectively. AP24534 was less potent in 2 FGFR wild type lines, HEC-1B and RL95.2, with GI50s of approximately 500 nM. To determine whether the anti-proliferative activity of AP24534 could be enhanced by an mTOR inhibitor, we treated cells with the combination of ridaforolimus and AP24534. The combination synergistically inhibited proliferation of both AN3CA and MFE-296 cells with combination index values of &lt;0.1 and 0.1–0.3, respectively. These effects were accompanied by dual inhibition of MAPK and mTOR signaling pathways. Further evaluation of AN3CA cells showed that the drug combination resulted in a near complete G1 arrest with no evidence of apoptosis. In an AN3CA xenograft tumor model AP24534 did not lead to tumor regression but had a strong dose-dependent effect on tumor growth, with 82% growth inhibition observed with a daily oral dose of 30 mg/kg. Consistent with in vitro results, a potent combinatorial effect was observed in vivo, with 43% tumor regression observed in mice dosed orally with 30 mg/kg AP24534 plus 1 mg/kg ridaforolimus.

Conclusion: AP24534 is a pan-FGFR inhibitor with potent activity in a variety of FGFR-driven tumor models. Dual inhibition of FGFR2 by AP24534 and mTOR by ridaforolimus leads to synergistic activity in FGFR2-driven endometrial cancer models in vitro, and tumor regression in the AN3CA xenograft model. These data provide support for the clinical testing of AP24534 in combination with ridaforolimus to treat FGFR2-driven endometrial cancers.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):B259.