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.
Subject(s)
Carcinoma, Hepatocellular/diagnostic imaging , Drug Resistance, Neoplasm , Liver Neoplasms/diagnostic imaging , Pyrans/pharmacology , Quinazolines/pharmacology , Receptor, Fibroblast Growth Factor, Type 4/genetics , Aged, 80 and over , Animals , Carcinoma, Hepatocellular/drug therapy , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/metabolism , Cell Line, Tumor , Female , Fibroblast Growth Factors/metabolism , Gene Expression Regulation, Neoplastic , Humans , Liver Neoplasms/drug therapy , Liver Neoplasms/genetics , Liver Neoplasms/metabolism , Male , Mice , Middle Aged , Models, Molecular , Mutation , Neoplasm Transplantation , Protein Domains , Receptor, Fibroblast Growth Factor, Type 4/chemistry , Receptor, Fibroblast Growth Factor, Type 4/metabolismABSTRACT
Multiple myeloma is a plasma cell neoplasm with an extremely variable clinical course. Animal models are needed to better understand its pathophysiology and for preclinical testing of potential therapeutic agents. Hematopoietic cells expressing the hypermorphic Rad50(s) allele show hematopoietic failure, which can be mitigated by the lack of a transcription factor, Mef/Elf4. However, we find that 70% of Mef(-/-)Rad50(s/s) mice die from multiple myeloma or other plasma cell neoplasms. These mice initially show an abnormal plasma cell proliferation and monoclonal protein production, and then develop anemia and a decreased bone mineral density. Tumor cells can be serially transplanted and according to array CGH and whole exome sequencing, the pathogenesis of plasma cell neoplasms in these mice is not linked to activation of a specific oncogene, or inactivation of a specific tumor suppressor. This model recapitulates the systemic manifestations of human plasma cell neoplasms, and implicates cooperativity between the Rad50(s) and Mef/Elf4 pathways in initiating myelomagenic mutations that promote plasma cell transformation.
Subject(s)
ATP-Binding Cassette Transporters/genetics , DNA-Binding Proteins/genetics , Multiple Myeloma/genetics , Phenotype , Transcription Factors/genetics , Acid Anhydride Hydrolases , Animals , Blood Cells/metabolism , Blood Cells/pathology , Blood Cells/physiology , Blood Cells/transplantation , Bone Density , Cell Proliferation , Cells, Cultured , Disease Models, Animal , Exome , Mice , Mice, Inbred C57BL , Multiple Myeloma/pathologyABSTRACT
t(8;21) is one of the most frequent chromosomal abnormalities observed in acute myeloid leukemia (AML). However, expression of AML1-ETO is not sufficient to induce transformation in vivo. Consistent with this observation, patients with this translocation harbor additional genetic abnormalities, suggesting a requirement for cooperating mutations. To better define the genetic landscape in AML and distinguish driver from passenger mutations, we compared the mutational profiles of AML1-ETO-driven mouse models of leukemia with the mutational profiles of human AML patients. We identified TET2 and PTPN11 mutations in both mouse and human AML and then demonstrated the ability of Tet2 loss and PTPN11 D61Y to initiate leukemogenesis in concert with expression of AML1-ETO in vivo. This integrative genetic profiling approach allowed us to accurately predict cooperating events in t(8;21)(+) AML in a robust and unbiased manner, while also revealing functional convergence in mouse and human AML.
Subject(s)
Alleles , Epistasis, Genetic , Genomics/methods , Leukemia, Myeloid, Acute/genetics , Animals , Cell Transformation, Neoplastic/genetics , Chromosomes, Human, Pair 21 , Chromosomes, Human, Pair 8 , Core Binding Factor Alpha 2 Subunit/genetics , Disease Models, Animal , Gene Expression Regulation, Leukemic , Gene Knockout Techniques , Humans , Mice , Mutation , Oncogene Proteins, Fusion/genetics , Phenotype , Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics , RUNX1 Translocation Partner 1 Protein , Translocation, GeneticABSTRACT
The AML1-ETO fusion transcription factor is generated by the t(8;21) translocation, which is present in approximately 4%-12% of adult and 12%-30% of pediatric acute myeloid leukemia (AML) patients. Both human and mouse models of AML have demonstrated that AML1-ETO is insufficient for leukemogenesis in the absence of secondary events. In this review, we discuss the pathogenetic insights that have been gained from identifying the various events that can cooperate with AML1-ETO to induce AML in vivo. We also discuss potential therapeutic strategies for t(8;21) positive AML that involve targeting the fusion protein itself, the proteins that bind to it, or the genes that it regulates. Recently published studies suggest that a targeted therapy for t(8;21) positive AML is feasible and may be coming sometime soon.
Subject(s)
Core Binding Factor Alpha 2 Subunit/genetics , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/therapy , Oncogene Proteins, Fusion/genetics , Transcription Factors/genetics , Translocation, Genetic , Animals , Biomarkers, Tumor/analysis , Cell Transformation, Neoplastic/genetics , Chromosomes, Human, Pair 21 , Chromosomes, Human, Pair 8 , Disease Models, Animal , Gene Expression Regulation, Leukemic , Genotype , Humans , Mice , Mice, Transgenic , Phenotype , RUNX1 Translocation Partner 1 ProteinABSTRACT
The chromosomal translocations found in acute myelogenous leukemia (AML) generate oncogenic fusion transcription factors with aberrant transcriptional regulatory properties. Although therapeutic targeting of most leukemia fusion proteins remains elusive, the posttranslational modifications that control their function could be targetable. We found that AML1-ETO, the fusion protein generated by the t(8;21) translocation, is acetylated by the transcriptional coactivator p300 in leukemia cells isolated from t(8;21) AML patients, and that this acetylation is essential for its self-renewal-promoting effects in human cord blood CD34(+) cells and its leukemogenicity in mouse models. Inhibition of p300 abrogates the acetylation of AML1-ETO and impairs its ability to promote leukemic transformation. Thus, lysine acetyltransferases represent a potential therapeutic target in AML.
Subject(s)
Cell Transformation, Neoplastic , Core Binding Factor Alpha 2 Subunit/metabolism , E1A-Associated p300 Protein/metabolism , Hematopoietic Stem Cells/cytology , Leukemia, Myeloid, Acute/metabolism , Lysine/metabolism , Oncogene Proteins, Fusion/metabolism , Acetylation , Animals , Cell Line , Cell Line, Tumor , Core Binding Factor Alpha 2 Subunit/chemistry , E1A-Associated p300 Protein/antagonists & inhibitors , Fetal Blood/cytology , Gene Expression Profiling , Hematopoietic Stem Cells/physiology , Humans , Leukemia, Myeloid, Acute/pathology , Mice , Mice, Inbred C57BL , Mutant Proteins/metabolism , Oncogene Proteins, Fusion/chemistry , Preleukemia/metabolism , Preleukemia/pathology , Protein Binding , Protein Interaction Domains and Motifs , Protein Processing, Post-Translational , RUNX1 Translocation Partner 1 Protein , Transcriptional Activation , Tumor Cells, CulturedABSTRACT
In this report we review the current knowledge of the interaction of RUNX1(AML1) with serine/threonine kinases, lysine and arginine methyltransferases, lysine acetyltransferases, and histone deacetylases. We also discuss the effect of RUNX1-ETO fusion gene on DNA methylation. RUNX1 post-transcriptional modification can affect its role in influencing differentiation and self-renewal of hematopoietic cells. The goal of these studies is to develop targets for improved leukemia therapy.
