TY - JOUR
T1 - Dual screen for efficacy and toxicity identifies HDAC inhibitor with distinctive activity spectrum for BAP1-mutant uveal melanoma
AU - Kuznetsoff, Jeffim N.
AU - Owens, Dawn A.
AU - Lopez, Andy
AU - Rodriguez, Daniel A.
AU - Chee, Nancy T.
AU - Kurtenbach, Stefan
AU - Bilbao, Daniel
AU - Roberts, Evan R.
AU - Volmar, Claude Henry
AU - Wahlestedt, Claes
AU - Brothers, Shaun P.
AU - Harbour, J. William
N1 - Funding Information:
This work was supported by DOD W81XWH-15–1-0578, Alcon Research Institute, Research to Prevent Blindness, Inc. Senior Scientific Investigator Award, and a generous gift from Dr. Mark J. Daily (to J.W. Harbour), NCI P30CA240139 (Sylvester Comprehensive Cancer Center), NEI P30EY014801 (Bascom Palmer Eye Institute), and Research to Prevent Blindness Unrestricted Grant (Bascom Palmer Eye Institute). We acknowledge the assistance of the Molecular Therapeutics Shared Resource (MTSR), Biostatistics and Bioinformatics Shared Resource (BBSR), Oncogenomics Shared Resources (OGSR), and Cancer Modeling Shared Resource (CMSR) of the Sylvester Comprehensive Cancer Center of the University of Miami Miller School of Medicine.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/2/1
Y1 - 2021/2/1
N2 - 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.
AB - 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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U2 - 10.1158/1541-7786.MCR-20-0434
DO - 10.1158/1541-7786.MCR-20-0434
M3 - Article
C2 - 33077485
AN - SCOPUS:85100385247
SN - 1541-7786
VL - 19
SP - 215
EP - 222
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 2
ER -