Abstract B259: Combined targeting of FGFR2 and mTOR by AP24534 and ridaforolimus results in synergistic antitumor activity in FGFR2-driven endometrial cancer models

• Published in: Molecular cancer therapeutics 2009-12, Vol.8 (12_Supplement), p.B259-B259
• Main 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.
• Format: Article
• Language: English
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.TARG-09-B259

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