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
Authors: Shemerly Mahmoud EL , Kellenberger Laurenz , Zanini Elisa , Lane Heidi , McSheehy Paul 
Published: June 2022

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, &lt;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.