Acute resistance to BET inhibitors remodels compensatory transcriptional programs via p300 coactivation
Abstract
Abstract Initial clinical trials with drugs targeting epigenetic modulators, such as bromodomain and extraterminal protein (BET) inhibitors, demonstrate modest results in acute myeloid leukemia (AML). A major reason for this involves an increased transcriptional plasticity within AML, which allows the cells to escape therapeutic pressure. In this study, we investigated the immediate epigenetic and transcriptional responses after BET inhibition and demonstrated that BET inhibitor–mediated release of bromodomain-containing protein 4 from chromatin is accompanied by acute compensatory feedback that attenuates downregulation or even increases the expression of specific transcriptional modules. This adaptation is marked at key AML maintenance genes and is mediated by p300, suggesting a rational therapeutic opportunity to improve outcomes by combining BET and p300 inhibition. p300 activity is required during all steps of resistance adaptation; however, the specific transcriptional programs that p300 regulates to induce resistance to BET inhibition differ, in part, between AML subtypes. As a consequence, in some AMLs, the requirement for p300 is highest during the earlier stages of resistance to BET inhibition, when p300 regulates transitional transcriptional patterns that allow leukemia-homeostatic adjustments. In other AMLs, p300 shapes a linear resistance to BET inhibition and remains critical throughout all stages of the evolution of resistance. Altogether, our study elucidates the mechanisms that underlie an “acute” state of resistance to BET inhibition, achieved through p300 activity, and how these mechanisms remodel to mediate “chronic” resistance. Importantly, our data also suggest that sequential treatment with BET and p300 inhibition may prevent resistance development, thereby improving outcomes.
Article Details
Authors (29)
Viral Shah
Global Modeling and Assimilation Office, NASA Goddard Space Flight Center
George Giotopoulos
Hikari Osaki
4Cambridge Stem Cell Institute, Cambridge, United Kingdom
Markus Meyerhöfer
1Department of Hematology and Oncology, Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
Eshwar Meduri
Aaron Gallego-Crespo
1Department of Hematology and Oncology, Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
Malte A. Behrendt
1Department of Hematology and Oncology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
Maria Saura-Panella
1Department of Hematology and Oncology, Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
Aarti Tarkar
6GlaxoSmithKline Research and Development, Collegeville, PA
Benedict Schubert
1Department of Hematology and Oncology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
Haiyang Yun
4Cambridge Stem Cell Institute, Cambridge, United Kingdom
Sarah J. Horton
Shuchi Agrawal-Singh
Patricia S. Haehnel
1Department of Hematology and Oncology, University Medical Center of the Johannes Gutenberg University, Mainz, Germany
Faisal Basheer
13Addenbrooke's Hospital, Department of Haematology, Cambridge, United Kingdom
Dave Lugo
8Adaptive Immunity and Immuno-epigenetics Research Unit, GlaxoSmithKline Research and Development, Stevenage, United Kingdom
Ioanna Eleftheriadou
6GlaxoSmithKline Research and Development, Collegeville, PA
Olena Barbash
6GlaxoSmithKline Research and Development, Collegeville, PA
Arindam Dhar
6GlaxoSmithKline Research and Development, Collegeville, PA
Michael W. M. Kühn
1Department of Hematology and Oncology, Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany
Borhane Guezguez
Matthias Theobald
Thomas Kindler
Paolo Gallipoli
Paul Yeh
5Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia
Mark A. Dawson
12Department of Clinical Haematology, Peter MacCallum Cancer Centre, Melbourne, Australia
Rab K. Prinjha
8Adaptive Immunity and Immuno-epigenetics Research Unit, GlaxoSmithKline Research and Development, Stevenage, United Kingdom
Brian J. P. Huntly
Daniel Sasca
1Department of Hematology and Oncology, Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany