論文 - 詳細
| RRC ID | 59962 |
|---|---|
| 著者 | Hatlen MA, Schmidt-Kittler O, Sherwin CA, Rozsahegyi E, Rubin N, Sheets MP, Kim JL, Miduturu C, Bifulco N, Brooijmans N, Shi H, Guzi T, Boral A, Lengauer C, Dorsch M, Kim RD, Kang YK, Wolf BB, Hoeflich KP. |
| タイトル | Acquired On-Target Clinical Resistance Validates FGFR4 as a Driver of Hepatocellular Carcinoma. |
| ジャーナル | Cancer Discov |
| 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. |
| 巻・号 | 9(12) |
| ページ | 1686-1695 |
| 公開日 | 2019-12-1 |
| DOI | 10.1158/2159-8290.CD-19-0367 |
| PII | 2159-8290.CD-19-0367 |
| PMID | 31575540 |
| MeSH | Aged, 80 and over Animals Carcinoma, Hepatocellular / diagnostic imaging* Carcinoma, Hepatocellular / drug therapy Carcinoma, Hepatocellular / genetics Carcinoma, Hepatocellular / metabolism Cell Line, Tumor Drug Resistance, Neoplasm* Female Fibroblast Growth Factors / metabolism Gene Expression Regulation, Neoplastic Humans Liver Neoplasms / diagnostic imaging* Liver Neoplasms / drug therapy Liver Neoplasms / genetics Liver Neoplasms / metabolism Male Mice Middle Aged Models, Molecular Mutation Neoplasm Transplantation Protein Domains Pyrans / pharmacology* Quinazolines / pharmacology* Receptor, Fibroblast Growth Factor, Type 4 / chemistry Receptor, Fibroblast Growth Factor, Type 4 / genetics* Receptor, Fibroblast Growth Factor, Type 4 / metabolism |
| IF | 26.37 |
| 引用数 | 6 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 15 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | HuH-7(RCB1942) |