fisogatinib (BLU-554)

Dysregulated FGFR4 activates the AKT/RYR2 axis, leading to tumor proliferation, invasion, and altered lipid metabolism in TNBC. FGFR4 inhibition could potentially serve as a novel therapeutic strategy for TNBC treatment.

Overall, our study revealed FGF19/FGFR4 as a new mechanism involved in the drug resistance of prolactinomas, and combination therapy targeting the pathway could be helpful for the treatment of BRC-induced drug-resistant prolactinomas.

Compound 11 displayed a nanomolar potency against Huh7 cell lines and high selectivity over FGFR1-3 that were comparable to that of fisogatinib (8) as a reference standard. Additionally, compound 11 demonstrated remarkable antitumor efficacy in the Huh7 and Hep3B HCC xenograft mouse model. Moreover, bioluminescence imaging experiments with the orthotopic mouse model support that compound 11 can be considered a promising candidate for treating HCC.

P1, N=146, Completed, Blueprint Medicines Corporation | Active, not recruiting --> Completed

Importantly, targeting FGF19 signaling with fisogatinib efficiently suppresses FGF19-induced liver metastasis in a mouse model. In summary, this study describes the mechanism by which FGF19 regulates CRLM, thereby providing a novel target for CRLM intervention.

Preliminary data showed that BLU-554 in combination with CS1001 is safe and effective for treatment of patients with locally advanced or metastatic HCC.

Furthermore, the combination of the FGFR4 inhibitor BLU-554 and the SRC inhibitor KX2-391 dramatically suppressed ELF4-mediated CRC metastasis. We demonstrated the essentiality of ELF4 in the metastatic process of CRC, and targeting the ELF4-relevant positive feedback circuit might represent a novel therapeutic strategy.

Efficacy studies were conducted in HCC xenograft models and mutant FGFR4-dependent xenograft models including a RMS PDX model harboring FGFR4 V550L mutation. ABSK012 demonstrated strong potency over multiple FGFR4 mutants that are insensitive to a first generation FGFR4 inhibitor BLU-554. ABSK012, presented here by Abbisko Therapeutics, is a highly potent, selective, and next-generation small molecule FGFR4 inhibitor overcoming FGFR4 mutations resistant to first-generation inhibitors. Its superior preclinical profile supports its fast-track development into clinic.

ETV4 is a prognostic biomarker, and anti-PD-L1 combined with FGFR4 inhibitor BLU-554 or MAPK inhibitor trametinib may be effective strategies to inhibit HCC metastasis.

P1, N=150, Active, not recruiting, Blueprint Medicines Corporation | Trial completion date: Dec 2022 --> Dec 2023