Acquired On-Target Clinical Resistance Validates FGFR4 as a Driver of Hepatocellular Carcinoma

Abstract

Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality worldwide with no clinically confi rmed oncogenic driver. Although preclinical studies implicate the FGF19 receptor FGFR4 in hepatocarcinogenesis, the dependence of human cancer on FGFR4 has not been demonstrated. Fisogatinib (BLU-554) is a potent and selective inhibitor of FGFR4 and demonstrates clinical benefi t and tumor regression in patients with HCC with aberrant FGF19 expression. Mutations were identifi ed in the gatekeeper and hinge-1 residues in the kinase domain of FGFR4 upon disease progression in 2 patients treated with fi sogatinib, which were confi rmed to mediate resistance in vitro and in vivo. A gatekeeper-agnostic, pan-FGFR inhibitor decreased HCC xenograft growth in the presence of these mutations, demonstrating continued FGF19-FGFR4 pathway dependence. These results validate FGFR4 as an oncogenic driver and warrant further therapeutic targeting of this kinase in the clinic. SIGNIFICANCE: Our study is the fi rst to demonstrate on-target FGFR4 kinase domain mutations as a mechanism of acquired clinical resistance to targeted therapy. This further establishes FGF19-FGFR4 pathway activation as an oncogenic driver. These fi ndings support further investigation of fi sogatinib in HCC and inform the profi le of potential next-generation inhibitors.

First-in-Human Phase I Study of Fisogatinib (BLU-554) Validates Aberrant FGF19 Signaling as a Driver Event in Hepatocellular Carcinoma

“…This phase I study with the highly potent and selective FGFR4 inhibitor fi sogatinib clinically validates the therapeutic potential of targeting the FGF19-FGFR4 pathway by demonstrating for the fi rst time that FGFR4 inhibition is tolerable and efficacious in advanced HCC expressing FGF19. The fi ndings of this study, together with the identifi cation of on-target fi sogatinib-resistance mutations in FGFR4 ( 22 ), confi rm the driver status of the FGF19-FGFR4 pathway in HCC with FGF19 overexpression.…”

“…1B). Fisogatinib also has a high affinity for FGFR4 that is approximately 100-fold higher than its affinity for FGFR1 and almost 1,000-fold higher than its affinity for FGFR2 and FGFR3 (22). Fisogatinib dose-dependently blocked the downstream signaling of FGFR4 in Hep3B cells that were further activated with exogenous FGF19 and in MDA-MB-453 cells with mutated and constitutively active FGFR4 (Supplementary Fig.…”

“…Fisogatinib covalently binds a unique cysteine residue found in FGFR4 (Cys 552; Supplementary Fig. S1A), thereby conferring a very high degree of selectivity for FGFR4 over other FGFR family members (22) and across the kinome (Fig. 1B).…”

Dissecting the Role of the FGF19-FGFR4 Signaling Pathway in Cancer Development and Progression

“…It has been reported that there are a number of amino-acid substitutions in the tyrosine kinase domains of FGFR4 (Dutra et al, 2015;Katoh, 2016). FGF401 (Weiss et al, 2019;Zhou et al, 2019), BLU9931 , and BLU-554 (Hatlen et al, 2019;Kim et al, 2019) have been reported to be the most highly potent and selective FGFR4 inhibitors. Representative FGFR4 inhibitors that are currently undergoing clinical trials were shown in Table 1.…”

Chemosensitivity of Patient-Derived Cancer Stem Cells Identifies Colorectal Cancer Patients with Potential Benefit from FGFR Inhibitor Therapy

“…It is well known that molecularly targeted therapy tends to induce specific and acquired resistance rather quickly in vitro and in vivo. Several recent clinical studies showed resistance mechanisms against FGFR inhibitors, i.e., FGFR gene point mutations and pathway activation such as MET [16,[38][39][40]. For example, EGFR suppresses FGFR3 expression in cells that are resistant to FGFR3 inhibitors and dominates the signal input to downstream pathways [41].…”