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Mol Cancer Res
2021 Feb 01;192:215-222. doi: 10.1158/1541-7786.MCR-20-0434.
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Dual Screen for Efficacy and Toxicity Identifies HDAC Inhibitor with Distinctive Activity Spectrum for BAP1-Mutant Uveal Melanoma.
Kuznetsoff JN, Owens DA, Lopez A, Rodriguez DA, Chee NT, Kurtenbach S, Bilbao D, Roberts ER, Volmar CH, Wahlestedt C, Brothers SP, Harbour JW.
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Drug screens leading to successful targeted therapies in cancer have been mainly based on cell viability assays identifying inhibitors of dominantly acting oncogenes. In contrast, there has been little success in discovering targeted therapies that reverse the effects of inactivating mutations in tumor-suppressor genes. BAP1 is one such tumor suppressor that is frequently inactivated in a variety of cancers, including uveal melanoma, renal cell carcinoma, and mesothelioma. Because BAP1 is an epigenetic transcriptional regulator of developmental genes, we designed a two-phase drug screen involving a cell-based rescue screen of transcriptional repression caused by BAP1 loss, followed by an in vivo screen of lead compounds for rescue of a BAP1-deficient phenotype with minimal toxicity in Xenopus embryos. The first screen identified 9 compounds, 8 of which were HDAC inhibitors. The second screen eliminated all except one compound due to inefficacy or toxicity. The resulting lead compound, quisinostat, has a distinctive activity spectrum, including high potency against HDAC4, which was recently shown to be a key target of BAP1. Quisinostat was further validated in a mouse model and found to prevent the growth of BAP1-mutant uveal melanomas. This innovative strategy demonstrates the potential for identifying therapeutic compounds that target tumor-suppressor mutations in cancer. IMPLICATIONS: Few drugs have been identified that target mutations in tumor suppressors. Using a novel 2-step screening approach, strategy, we identified quisinostat as a candidate for therapy in BAP1-mutant uveal melanoma. HDAC4 is implicated as a key target in uveal melanoma and perhaps other BAP1-mutant cancers.
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Arts,
JNJ-26481585, a novel "second-generation" oral histone deacetylase inhibitor, shows broad-spectrum preclinical antitumoral activity.
2009,
Pubmed Atmaca,
Valproic acid (VPA) in patients with refractory advanced cancer: a dose escalating phase I clinical trial.
2007,
Pubmed Bailey,
Comprehensive Characterization of Cancer Driver Genes and Mutations.
2018,
Pubmed Bhullar,
Kinase-targeted cancer therapies: progress, challenges and future directions.
2018,
Pubmed Bott,
The nuclear deubiquitinase BAP1 is commonly inactivated by somatic mutations and 3p21.1 losses in malignant pleural mesothelioma.
2011,
Pubmed Campagne,
BAP1 complex promotes transcription by opposing PRC1-mediated H2A ubiquitylation.
2019,
Pubmed Carbone,
BAP1 and cancer.
2013,
Pubmed Dobin,
STAR: ultrafast universal RNA-seq aligner.
2013,
Pubmed Field,
Punctuated evolution of canonical genomic aberrations in uveal melanoma.
2018,
Pubmed Gonçalves,
Decitabine limits escape from MEK inhibition in uveal melanoma.
2020,
Pubmed Gotwals,
Prospects for combining targeted and conventional cancer therapy with immunotherapy.
2017,
Pubmed Harbour,
Frequent mutation of BAP1 in metastasizing uveal melanomas.
2010,
Pubmed Heijkants,
Combined inhibition of CDK and HDAC as a promising therapeutic strategy for both cutaneous and uveal metastatic melanoma.
2018,
Pubmed Janczura,
Inhibition of HDAC3 reverses Alzheimer's disease-related pathologies in vitro and in the 3xTg-AD mouse model.
2018,
Pubmed Jerby-Arnon,
Predicting cancer-specific vulnerability via data-driven detection of synthetic lethality.
2014,
Pubmed Jiao,
Exome sequencing identifies frequent inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic cholangiocarcinomas.
2013,
Pubmed Kuznetsov,
BAP1 regulates epigenetic switch from pluripotency to differentiation in developmental lineages giving rise to BAP1-mutant cancers.
2019,
Pubmed
,
Xenbase Landreville,
Histone deacetylase inhibitors induce growth arrest and differentiation in uveal melanoma.
2012,
Pubmed Li,
RSEM: accurate transcript quantification from RNA-Seq data with or without a reference genome.
2011,
Pubmed Liu,
Targeting tumor suppressor genes for cancer therapy.
2015,
Pubmed Love,
Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2.
2014,
Pubmed Morris,
Therapeutic targeting of tumor suppressor genes.
2015,
Pubmed Mustafi,
Vitamin C Sensitizes Melanoma to BET Inhibitors.
2018,
Pubmed Némati,
Establishment and characterization of a panel of human uveal melanoma xenografts derived from primary and/or metastatic tumors.
2010,
Pubmed Peña-Llopis,
BAP1 loss defines a new class of renal cell carcinoma.
2012,
Pubmed Scheuermann,
Histone H2A deubiquitinase activity of the Polycomb repressive complex PR-DUB.
2010,
Pubmed Srinivasan,
Synthetic lethality in malignant pleural mesothelioma with PARP1 inhibition.
2017,
Pubmed Vasan,
A view on drug resistance in cancer.
2019,
Pubmed Volmar,
M344 promotes nonamyloidogenic amyloid precursor protein processing while normalizing Alzheimer's disease genes and improving memory.
2017,
Pubmed Wiederschain,
Single-vector inducible lentiviral RNAi system for oncology target validation.
2009,
Pubmed Yang,
Treatment of uveal melanoma: where are we now?
2018,
Pubmed Zeier,
Bromodomain inhibitors regulate the C9ORF72 locus in ALS.
2015,
Pubmed Zhang,
A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays.
1999,
Pubmed
