@article{806a5bd52946430d995bf717aca6cdf3,
title = "Network-based assessment of HDAC6 activity predicts preclinical and clinical responses to the HDAC6 inhibitor ricolinostat in breast cancer",
abstract = "Inhibiting individual histone deacetylase (HDAC) is emerging as well-tolerated anticancer strategy compared with pan-HDAC inhibitors. Through preclinical studies, we demonstrated that the sensitivity to the leading HDAC6 inhibitor (HDAC6i) ricolinstat can be predicted by a computational network-based algorithm (HDAC6 score). Analysis of ~3,000 human breast cancers (BCs) showed that ~30% of them could benefice from HDAC6i therapy. Thus, we designed a phase 1b dose-escalation clinical trial to evaluate the activity of ricolinostat plus nab-paclitaxel in patients with metastatic BC (MBC) (NCT02632071). Study results showed that the two agents can be safely combined, that clinical activity is identified in patients with HR+/HER2− disease and that the HDAC6 score has potential as predictive biomarker. Analysis of other tumor types also identified multiple cohorts with predicted sensitivity to HDAC6i{\textquoteright}s. Mechanistically, we have linked the anticancer activity of HDAC6i{\textquoteright}s to their ability to induce c-Myc hyperacetylation (ac-K148) promoting its proteasome-mediated degradation in sensitive cancer cells.",
author = "Zeleke, {Tizita Z.} and Qingfei Pan and Codruta Chiuzan and Maika Onishi and Yuxin Li and Haiyan Tan and Alvarez, {Mariano J.} and Erin Honan and Min Yang and Chia, {Pei Ling} and Partha Mukhopadhyay and Sean Kelly and Ruby Wu and Kathleen Fenn and Trivedi, {Meghna S.} and Melissa Accordino and Crew, {Katherine D.} and Hershman, {Dawn L.} and Matthew Maurer and Simon Jones and Anthony High and Junmin Peng and Andrea Califano and Kevin Kalinsky and Jiyang Yu and Jose Silva",
note = "Funding Information: We thank members of the Silva and Yu laboratories for advice generating this manuscript and for technical assistance, including D. Alsina-Beauchamp and R. Werner (Silva lab) and X. Dong, K.-K. Yan and L. Ding (Yu lab). We also thank S.-W. Lee from Mount Sinai{\textquoteright}s CCMS core for technical assistance with mouse xenograft experiments. We also thank K. A. Laycock for scientific editing of the manuscript. This research was partially funded through the DOD Breakthrough award 151500 (J.S.); ALSAC (J.Y.); National Institutes of Health grants R01 CA153233 (J.S.), R01 CA153233–supplement (T.Z.Z.), R01 GM134382 (J.Y)., U01 CA217858 (A.C.), S10 OD012351 (A.C.) and S10 OD021764 (A.C.); and the Irving Scholar program (K.K.). Funding Information: We thank members of the Silva and Yu laboratories for advice generating this manuscript and for technical assistance, including D. Alsina-Beauchamp and R. Werner (Silva lab) and X. Dong, K.-K. Yan and L. Ding (Yu lab). We also thank S.-W. Lee from Mount Sinai{\textquoteright}s CCMS core for technical assistance with mouse xenograft experiments. We also thank K. A. Laycock for scientific editing of the manuscript. This research was partially funded through the DOD Breakthrough award 151500 (J.S.); ALSAC (J.Y.); National Institutes of Health grants R01 CA153233 (J.S.), R01 CA153233–supplement (T.Z.Z.), R01 GM134382 (J.Y)., U01 CA217858 (A.C.), S10 OD012351 (A.C.) and S10 OD021764 (A.C.); and the Irving Scholar program (K.K.). Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2023",
month = feb,
doi = "10.1038/s43018-022-00489-5",
language = "English",
volume = "4",
pages = "257--275",
journal = "Nature Cancer",
issn = "2662-1347",
publisher = "Nature Research",
number = "2",
}