TKI258 is an effective multi-targeted receptor tyrosine kinase (RTK) inhibitor against xenograft models of human melanoma.

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA 3258 TKI258 (formerly CHIR-258) is an oral, multi-targeted RTK inhibitor of FGFR, VEGFR, PDGFRβ, FLT3 and c-KIT. Given that FGFR 1-4 and their FGF ligands are implicated in the pathogenesis of melanoma, we investigated TKI258 efficacy in melanoma models, based on it’s potential activity against both tumor cells via inhibition of FGFR, and against the tumor vasculature by targeting FGFR, VEGFR and PDGFRβ. In vitro activity of TKI258 was tested in clonogenic assays against a panel of melanoma cell lines and limited passage human melanoma cells propagated in mice. All melanoma cell lines were characterized for expression of FGFR1-4 and mutational status of B-Raf or Ras. In the in vitro clonogenic assays on soft agar, TKI258 activity was observed in all melanoma cells regardless of FGFR1-4 expression levels, or wild-type/mutant Ras/B-Raf status. In vivo efficacy was evaluated in two different subcutaneous melanoma xenograft models: CHL-1 (WT K-Ras and WT B-Raf) and A375M (mutant B-Raf) in athymic nude mice. These xenograft models have similar patterns of expression of FGFR1-4, but differ in Ras/Raf pathway status. Daily oral administration of TKI258 at doses that inhibit FGFR signaling in vivo resulted in significant tumor growth inhibition of both CHL-1 and A375M tumor xenograft models. Antitumor activity of TKI258 was also evaluated in vivo in combination with the chemotherapeutic agents carboplatin and paclitaxel, which are used clinically to treat melanoma. Compared to monotherapy, the combination of TKI258 with carboplatin plus paclitaxel resulted in enhanced activity against both CHL-1 and A375M tumors and was well tolerated. In the CHL-1 model, treatment with carboplatin plus paclitaxel at maximum tolerated doses showed no tumor growth inhibition (TGI), whereas TKI258 therapy demonstrated approximately 44% TGI. The combination of all three agents exhibited 70% TGI. In the A375 model, animals dosed with the carboplatin + paclitaxel combination resulted in 35% TGI, TKI258 treatment alone showed 58% TGI and the combination of all three agents resulted in 73% TGI. In conclusion, anti-tumor activity of TKI258 in these models is likely due to multiple mechanisms, including inhibition of FGFR 1-4 and/or additional TKI258 targets expressed by these melanoma cell lines, and it’s anti-angiogenic activity via inhibition of VEGFR and PDGFRβ. These results demonstrate that TKI258 is effective as a single agent and in combination with chemotherapy in preclinical melanoma models, thus providing a basis for TKI258 clinical trials in melanoma. *equal contributing authors