Therapeutic targeting of EP300/CBP by bromodomain inhibition in hematologic malignancies

Luciano Nicosia; Gary J Spencer; Nigel Brooks; Fabio M R Amaral; Naseer J Basma; John A Chadwick; Bradley Revell; Bettina Wingelhofer; Alba Maiques-Diaz; Oliver Sinclair; Francesco Camera; Filippo Ciceri; Daniel H Wiseman; Neil Pegg; Will West; Tomasz Knurowski; Kris Frese; Karen Clegg; Victoria L Campbell; James Cavet; Mhairi Copland; Emma Searle; Tim C P Somervaille

doi:10.1016/j.ccell.2023.11.001

Therapeutic targeting of EP300/CBP by bromodomain inhibition in hematologic malignancies

Luciano Nicosia, Gary J Spencer, Nigel Brooks, Fabio M R Amaral, Naseer J Basma, John A Chadwick, Bradley Revell, Bettina Wingelhofer, Alba Maiques-Diaz, Oliver Sinclair, Francesco Camera, Filippo Ciceri, Daniel H Wiseman, Neil Pegg, Will West, Tomasz Knurowski, Kris Frese, Karen Clegg, Victoria L Campbell, James CavetMhairi Copland, Emma Searle, Tim C P Somervaille

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

Abstract

CCS1477 (inobrodib) is a potent, selective EP300/CBP bromodomain inhibitor which induces cell-cycle arrest and differentiation in hematologic malignancy model systems. In myeloid leukemia cells, it promotes rapid eviction of EP300/CBP from an enhancer subset marked by strong MYB occupancy and high H3K27 acetylation, with downregulation of the subordinate oncogenic network and redistribution to sites close to differentiation genes. In myeloma cells, CCS1477 induces eviction of EP300/CBP from FGFR3, the target of the common (4; 14) translocation, with redistribution away from IRF4-occupied sites to TCF3/E2A-occupied sites. In a subset of patients with relapsed or refractory disease, CCS1477 monotherapy induces differentiation responses in AML and objective responses in heavily pre-treated multiple myeloma. In vivo preclinical combination studies reveal synergistic responses to treatment with standard-of-care agents. Thus, CCS1477 exhibits encouraging preclinical and early-phase clinical activity by disrupting recruitment of EP300/CBP to enhancer networks occupied by critical transcription factors.

Original language	English
Pages (from-to)	2136-2153.e13
Journal	Cancer Cell
Volume	41
Issue number	12
Early online date	22 Nov 2023
DOIs	https://doi.org/10.1016/j.ccell.2023.11.001
Publication status	Published - 11 Dec 2023

Keywords

Humans
Nuclear Proteins
Cell Line, Tumor
Transcription Factors
Protein Domains
Hematologic Neoplasms/drug therapy
E1A-Associated p300 Protein

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Nicosia, L., Spencer, G. J., Brooks, N., Amaral, F. M. R., Basma, N. J., Chadwick, J. A., Revell, B., Wingelhofer, B., Maiques-Diaz, A., Sinclair, O., Camera, F., Ciceri, F., Wiseman, D. H., Pegg, N., West, W., Knurowski, T., Frese, K., Clegg, K., Campbell, V. L., ... Somervaille, T. C. P. (2023). Therapeutic targeting of EP300/CBP by bromodomain inhibition in hematologic malignancies. Cancer Cell, 41(12), 2136-2153.e13. https://doi.org/10.1016/j.ccell.2023.11.001

@article{c2958e1ea6ee4b2cb38db8bffab3e0d8,

title = "Therapeutic targeting of EP300/CBP by bromodomain inhibition in hematologic malignancies",

abstract = "CCS1477 (inobrodib) is a potent, selective EP300/CBP bromodomain inhibitor which induces cell-cycle arrest and differentiation in hematologic malignancy model systems. In myeloid leukemia cells, it promotes rapid eviction of EP300/CBP from an enhancer subset marked by strong MYB occupancy and high H3K27 acetylation, with downregulation of the subordinate oncogenic network and redistribution to sites close to differentiation genes. In myeloma cells, CCS1477 induces eviction of EP300/CBP from FGFR3, the target of the common (4; 14) translocation, with redistribution away from IRF4-occupied sites to TCF3/E2A-occupied sites. In a subset of patients with relapsed or refractory disease, CCS1477 monotherapy induces differentiation responses in AML and objective responses in heavily pre-treated multiple myeloma. In vivo preclinical combination studies reveal synergistic responses to treatment with standard-of-care agents. Thus, CCS1477 exhibits encouraging preclinical and early-phase clinical activity by disrupting recruitment of EP300/CBP to enhancer networks occupied by critical transcription factors.",

keywords = "Humans, Nuclear Proteins, Cell Line, Tumor, Transcription Factors, Protein Domains, Hematologic Neoplasms/drug therapy, E1A-Associated p300 Protein",

author = "Luciano Nicosia and Spencer, \{Gary J\} and Nigel Brooks and Amaral, \{Fabio M R\} and Basma, \{Naseer J\} and Chadwick, \{John A\} and Bradley Revell and Bettina Wingelhofer and Alba Maiques-Diaz and Oliver Sinclair and Francesco Camera and Filippo Ciceri and Wiseman, \{Daniel H\} and Neil Pegg and Will West and Tomasz Knurowski and Kris Frese and Karen Clegg and Campbell, \{Victoria L\} and James Cavet and Mhairi Copland and Emma Searle and Somervaille, \{Tim C P\}",

year = "2023",

month = dec,

day = "11",

doi = "10.1016/j.ccell.2023.11.001",

language = "English",

volume = "41",

pages = "2136--2153.e13",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "12",

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Nicosia, L, Spencer, GJ, Brooks, N, Amaral, FMR, Basma, NJ, Chadwick, JA, Revell, B, Wingelhofer, B, Maiques-Diaz, A, Sinclair, O, Camera, F, Ciceri, F, Wiseman, DH, Pegg, N, West, W, Knurowski, T, Frese, K, Clegg, K, Campbell, VL, Cavet, J, Copland, M, Searle, E & Somervaille, TCP 2023, 'Therapeutic targeting of EP300/CBP by bromodomain inhibition in hematologic malignancies', Cancer Cell, vol. 41, no. 12, pp. 2136-2153.e13. https://doi.org/10.1016/j.ccell.2023.11.001

TY - JOUR

T1 - Therapeutic targeting of EP300/CBP by bromodomain inhibition in hematologic malignancies

AU - Nicosia, Luciano

AU - Spencer, Gary J

AU - Brooks, Nigel

AU - Amaral, Fabio M R

AU - Basma, Naseer J

AU - Chadwick, John A

AU - Revell, Bradley

AU - Wingelhofer, Bettina

AU - Maiques-Diaz, Alba

AU - Sinclair, Oliver

AU - Camera, Francesco

AU - Ciceri, Filippo

AU - Wiseman, Daniel H

AU - Pegg, Neil

AU - West, Will

AU - Knurowski, Tomasz

AU - Frese, Kris

AU - Clegg, Karen

AU - Campbell, Victoria L

AU - Cavet, James

AU - Copland, Mhairi

AU - Searle, Emma

AU - Somervaille, Tim C P

PY - 2023/12/11

Y1 - 2023/12/11

N2 - CCS1477 (inobrodib) is a potent, selective EP300/CBP bromodomain inhibitor which induces cell-cycle arrest and differentiation in hematologic malignancy model systems. In myeloid leukemia cells, it promotes rapid eviction of EP300/CBP from an enhancer subset marked by strong MYB occupancy and high H3K27 acetylation, with downregulation of the subordinate oncogenic network and redistribution to sites close to differentiation genes. In myeloma cells, CCS1477 induces eviction of EP300/CBP from FGFR3, the target of the common (4; 14) translocation, with redistribution away from IRF4-occupied sites to TCF3/E2A-occupied sites. In a subset of patients with relapsed or refractory disease, CCS1477 monotherapy induces differentiation responses in AML and objective responses in heavily pre-treated multiple myeloma. In vivo preclinical combination studies reveal synergistic responses to treatment with standard-of-care agents. Thus, CCS1477 exhibits encouraging preclinical and early-phase clinical activity by disrupting recruitment of EP300/CBP to enhancer networks occupied by critical transcription factors.

AB - CCS1477 (inobrodib) is a potent, selective EP300/CBP bromodomain inhibitor which induces cell-cycle arrest and differentiation in hematologic malignancy model systems. In myeloid leukemia cells, it promotes rapid eviction of EP300/CBP from an enhancer subset marked by strong MYB occupancy and high H3K27 acetylation, with downregulation of the subordinate oncogenic network and redistribution to sites close to differentiation genes. In myeloma cells, CCS1477 induces eviction of EP300/CBP from FGFR3, the target of the common (4; 14) translocation, with redistribution away from IRF4-occupied sites to TCF3/E2A-occupied sites. In a subset of patients with relapsed or refractory disease, CCS1477 monotherapy induces differentiation responses in AML and objective responses in heavily pre-treated multiple myeloma. In vivo preclinical combination studies reveal synergistic responses to treatment with standard-of-care agents. Thus, CCS1477 exhibits encouraging preclinical and early-phase clinical activity by disrupting recruitment of EP300/CBP to enhancer networks occupied by critical transcription factors.

KW - Humans

KW - Nuclear Proteins

KW - Cell Line, Tumor

KW - Transcription Factors

KW - Protein Domains

KW - Hematologic Neoplasms/drug therapy

KW - E1A-Associated p300 Protein

UR - https://www.scopus.com/pages/publications/85179030914

UR - https://www.mendeley.com/catalogue/7037708a-3807-3d5f-9fe6-d1ed9230fea5/

U2 - 10.1016/j.ccell.2023.11.001

DO - 10.1016/j.ccell.2023.11.001

M3 - Article

C2 - 37995682

SN - 1535-6108

VL - 41

SP - 2136-2153.e13

JO - Cancer Cell

JF - Cancer Cell

IS - 12

ER -

Therapeutic targeting of EP300/CBP by bromodomain inhibition in hematologic malignancies

Abstract

Keywords

UN SDGs

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