Network-based assessment of HDAC6 activity predicts preclinical and clinical responses to the HDAC6 inhibitor ricolinostat in breast cancer

Tizita Z. Zeleke; Qingfei Pan; Codruta Chiuzan; Maika Onishi; Yuxin Li; Haiyan Tan; Mariano J. Alvarez; Erin Honan; Min Yang; Pei Ling Chia; Partha Mukhopadhyay; Sean Kelly; Ruby Wu; Kathleen Fenn; Meghna S. Trivedi; Melissa Accordino; Katherine D. Crew; Dawn L. Hershman; Matthew Maurer; Simon Jones; Anthony High; Junmin Peng; Andrea Califano; Kevin Kalinsky; Jiyang Yu; Jose Silva

doi:10.1038/s43018-022-00489-5

Network-based assessment of HDAC6 activity predicts preclinical and clinical responses to the HDAC6 inhibitor ricolinostat in breast cancer

Tizita Z. Zeleke, Qingfei Pan, Codruta Chiuzan, Maika Onishi, Yuxin Li, Haiyan Tan, Mariano J. Alvarez, Erin Honan, Min Yang, Pei Ling Chia, Partha Mukhopadhyay, Sean Kelly, Ruby Wu, Kathleen Fenn, Meghna S. Trivedi, Melissa Accordino, Katherine D. Crew, Dawn L. Hershman, Matthew Maurer, Simon JonesAnthony High, Junmin Peng, Andrea Califano, Kevin Kalinsky, Jiyang Yu, Jose Silva

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

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’s. Mechanistically, we have linked the anticancer activity of HDAC6i’s to their ability to induce c-Myc hyperacetylation (ac-K148) promoting its proteasome-mediated degradation in sensitive cancer cells.

Original language	English
Pages (from-to)	257-275
Number of pages	19
Journal	Nature Cancer
Volume	4
Issue number	2
DOIs	https://doi.org/10.1038/s43018-022-00489-5
State	Published - Feb 2023

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Zeleke, T. Z., Pan, Q., Chiuzan, C., Onishi, M., Li, Y., Tan, H., Alvarez, M. J., Honan, E., Yang, M., Chia, P. L., Mukhopadhyay, P., Kelly, S., Wu, R., Fenn, K., Trivedi, M. S., Accordino, M., Crew, K. D., Hershman, D. L., Maurer, M., ... Silva, J. (2023). Network-based assessment of HDAC6 activity predicts preclinical and clinical responses to the HDAC6 inhibitor ricolinostat in breast cancer. Nature Cancer, 4(2), 257-275. https://doi.org/10.1038/s43018-022-00489-5

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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 = "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",

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Zeleke, TZ, Pan, Q, Chiuzan, C, Onishi, M, Li, Y, Tan, H, Alvarez, MJ, Honan, E, Yang, M, Chia, PL, Mukhopadhyay, P, Kelly, S, Wu, R, Fenn, K, Trivedi, MS, Accordino, M, Crew, KD, Hershman, DL, Maurer, M, Jones, S, High, A, Peng, J, Califano, A, Kalinsky, K, Yu, J & Silva, J 2023, 'Network-based assessment of HDAC6 activity predicts preclinical and clinical responses to the HDAC6 inhibitor ricolinostat in breast cancer', Nature Cancer, vol. 4, no. 2, pp. 257-275. https://doi.org/10.1038/s43018-022-00489-5

TY - JOUR

T1 - Network-based assessment of HDAC6 activity predicts preclinical and clinical responses to the HDAC6 inhibitor ricolinostat in breast cancer

AU - Zeleke, Tizita Z.

AU - Pan, Qingfei

AU - Chiuzan, Codruta

AU - Onishi, Maika

AU - Li, Yuxin

AU - Tan, Haiyan

AU - Alvarez, Mariano J.

AU - Honan, Erin

AU - Yang, Min

AU - Chia, Pei Ling

AU - Mukhopadhyay, Partha

AU - Kelly, Sean

AU - Wu, Ruby

AU - Fenn, Kathleen

AU - Trivedi, Meghna S.

AU - Accordino, Melissa

AU - Crew, Katherine D.

AU - Hershman, Dawn L.

AU - Maurer, Matthew

AU - Jones, Simon

AU - High, Anthony

AU - Peng, Junmin

AU - Califano, Andrea

AU - Kalinsky, Kevin

AU - Yu, Jiyang

AU - Silva, Jose

PY - 2023/2

Y1 - 2023/2

N2 - 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’s. Mechanistically, we have linked the anticancer activity of HDAC6i’s to their ability to induce c-Myc hyperacetylation (ac-K148) promoting its proteasome-mediated degradation in sensitive cancer cells.

AB - 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’s. Mechanistically, we have linked the anticancer activity of HDAC6i’s to their ability to induce c-Myc hyperacetylation (ac-K148) promoting its proteasome-mediated degradation in sensitive cancer cells.

UR - http://www.scopus.com/inward/record.url?scp=85145169966&partnerID=8YFLogxK

U2 - 10.1038/s43018-022-00489-5

DO - 10.1038/s43018-022-00489-5

M3 - Article

C2 - 36585452

AN - SCOPUS:85145169966

SN - 2662-1347

VL - 4

SP - 257

EP - 275

JO - Nature Cancer

JF - Nature Cancer

IS - 2

ER -

Network-based assessment of HDAC6 activity predicts preclinical and clinical responses to the HDAC6 inhibitor ricolinostat in breast cancer

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