1. Academic Validation
  2. Acquired On-Target Clinical Resistance Validates FGFR4 as a Driver of Hepatocellular Carcinoma

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

  • Cancer Discov. 2019 Dec;9(12):1686-1695. doi: 10.1158/2159-8290.CD-19-0367.
Megan A Hatlen  # 1 Oleg Schmidt-Kittler  # 1 Cori Ann Sherwin 1 Emily Rozsahegyi 1 Nooreen Rubin 1 Michael P Sheets 1 Joseph L Kim 1 Chandrasekhar Miduturu 1 Neil Bifulco 1 Natasja Brooijmans 1 Hongliang Shi 1 Timothy Guzi 1 Andy Boral 1 Christoph Lengauer 1 Marion Dorsch 1 Richard D Kim 2 Yoon-Koo Kang 3 Beni B Wolf 1 Klaus P Hoeflich 4
Affiliations

Affiliations

  • 1 Blueprint Medicines Corporation, Cambridge, Massachusetts.
  • 2 H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
  • 3 Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
  • 4 Blueprint Medicines Corporation, Cambridge, Massachusetts. khoeflich@blueprintmedicines.com.
  • # Contributed equally.
Abstract

Hepatocellular carcinoma (HCC) is a leading cause of Cancer mortality worldwide with no clinically confirmed 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 benefit and tumor regression in patients with HCC with aberrant FGF19 expression. Mutations were identified in the gatekeeper and hinge-1 residues in the kinase domain of FGFR4 upon disease progression in 2 patients treated with fisogatinib, which were confirmed 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 first 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 findings support further investigation of fisogatinib in HCC and inform the profile of potential next-generation inhibitors.See related commentary by Subbiah and Pal, p. 1646.This article is highlighted in the In This Issue feature, p. 1631.

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