Abstract 5501: Derazantinib, an FGFR1-3 inhibitor, inhibits CSF1R in macrophages and tumor cell lines, and synergizes with a PDL1-antibody in an FGFR-driven murine syngeneic model

Abstract

Introduction: Derazantinib (DZB), an inhibitor of the fibroblast growth factor receptors 1-3 (FGFR1-3), is in phase-2 clinical trials for cholangiocarcinoma, urothelial and gastric cancer for tumors with FGFR-amplifications, fusions and mutations. DZB has similar potency against colony-stimulating factor receptor-1 (CSF1R); a protein important in the function of M2 tumor-associated macrophages (M2-TAMs). M2-TAMs cause an immunosuppressive environment in solid tumors that decrease the effectiveness of checkpoint inhibitors such as PD-1/PD-L1 inhibitors, and promote angiogenesis and metastasis. Methods: Proliferating mouse macrophage cells (RAW264.7) and human tumor cells (GDM1 and DEL) were pre-treated for 1h with compounds. Cells were treated with/out CSF1 (10ng/ml) for 5min, lysed and analyzed by western blot. Images were quantified using the EvolutionCapt program. Murine 4T1 breast tumor cells were grown orthotopically in syngeneic Balb/c mice, Karpass299 lymphoma cells s.c. in CB17/Scid mice, and gastric (GA0119) and cholangiocarcinoma (CC6604)-PDX in athymic Balb/c mice. One 4T1 experiment used stably transfected luciferased (4T1-Luc) cells. DZB (65-75 mg/kg) and another FGFR-inhibitor, pemigatinib (1 mg/kg) were dosed daily, orally, and the murine PDL1-Antibody (PDL1-Ab) was dosed at 5-10 mg/kg, i.p., 2qw. Efficacy was assessed as a dT/C, and metastases were determined by counting nodules and/or bioluminescence ex vivo. Results: DZB inhibited p-CSF1R in cultured cells with mean±SEM IC50s of 307, <500, 54nM for RAW264.7, GDM1, DEL cells, respectively. These IC50s were similar to the potency of DZB against the HeLa cell-line transiently infected with FGFR2 (107nM), thus confirming kinase assays that indicated similar sensitivity of FGFR1-3 and CSF1R to DZB. Other FGFR-inhibitors, including pemigatinib, which has no CSF1R activity, were without significant effect. In 3 tumor xenograft models with reported expression/amplification of CSF1R, DZB had a mild inhibitory effect (ΔT/C=0.67±0.05), while pemigatinib had no efficacy (ΔT/C=1.02±0.16); mean±SEM. However, in these xenografts we were unable to detect p-CSF1R. In the FGFR-driven syngeneic tumor-model, 4T1, DZB was highly efficacious causing tumor-stasis. The PDL1-Ab was without efficacy in this model, but in combination with DZB, increased efficacy against the primary tumor, and more strongly against the liver and lung metastases. PD-analyses are ongoing to explore the mechanism of this interaction. Conclusion: DZB is a potent inhibitor of CSF1R in vitro. In combination with a murine PDL1-Ab, DZB showed a positive interaction in the orthotopic syngeneic breast tumor model, 4T1, against both the primary tumor and metastases. These data support clinical trials in which DZB is combined with the PDL1-Ab, atezolizumab (NCT04604132, NCT04045613). Citation Format: Mahmoud EL Shemerly, Laurenz Kellenberger, Elisa Zanini, Heidi Lane, Paul McSheehy. Derazantinib, an FGFR1-3 inhibitor, inhibits CSF1R in macrophages and tumor cell lines, and synergizes with a PDL1-antibody in an FGFR-driven murine syngeneic model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5501.

The fibroblast growth factor receptor inhibitor, derazantinib, has strong efficacy in human gastric tumor models and synergizes with paclitaxel in vivo

“…This may be because changes in TAM type are very dynamic or that the measurements that we used were not sufficiently specific, for example, CD68 and CD163 antigens are also used to identify the M2 type [28]. Furthermore, downstream effects on immune activation that are an expected consequence of affecting the M2/M1 ratio, such as increases in natural killer cells and/or cytotoxic T-cells, cannot happen in xenograft models, although we have observed these changes in syngeneic models [3]. The most consistent and significant PD-change observed in these GC models in vivo was a decrease in the number of proliferating cells, as assessed by Ki67, which was greatest for the combination.…”

“…Derazantinib (DZB) has been shown to be an ATP-competitive inhibitor of FGFR1–3 with activity in the nM range in kinases assays with reduced activity against FGFR4 [2]. Cellular model systems using COS-1 and Ba/F3 confirmed the molecular target as FGFR as did subsequent experiments using HeLa cells transiently transfected with FGFR2 [3]. The compound selectively inhibits tumor cells with significant FGFR1–3 aberrations, and when those cells were grown in nude mice as solid tumors, growth inhibition was observed along with decreased signaling in the mitogen activated protein kinase pathway [2].…”