BET bromodomain inhibition potentiates radiosensitivity in models of H3K27-altered diffuse midline glioma

Jun Watanabe; Matthew R. Clutter; Michael J. Gullette; Takahiro Sasaki; Eita Uchida; Savneet Kaur; Yan Mo; Kouki Abe; Yukitomo Ishi; Nozomu Takata; Manabu Natsumeda; Samantha Gadd; Zhiguo Zhang; Oren J. Becher; Rintaro Hashizume

doi:10.1172/JCI174794

BET bromodomain inhibition potentiates radiosensitivity in models of H3K27-altered diffuse midline glioma

Jun Watanabe, Matthew R. Clutter, Michael J. Gullette, Takahiro Sasaki, Eita Uchida, Savneet Kaur, Yan Mo, Kouki Abe, Yukitomo Ishi, Nozomu Takata, Manabu Natsumeda, Samantha Gadd, Zhiguo Zhang, Oren J. Becher^*, Rintaro Hashizume^*

^*Corresponding author for this work

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

3 Scopus citations

Abstract

Diffuse midline glioma (DMG) H3K27-altered is one of the most malignant childhood cancers. Radiation therapy remains the only effective treatment yet provides a 5-year survival rate of only 1%. Several clinical trials have attempted to enhance radiation antitumor activity using radiosensitizing agents, although none have been successful. Given this, there is a critical need for identifying effective therapeutics to enhance radiation sensitivity for the treatment of DMG. Using high-throughput radiosensitivity screening, we identified bromo- and extraterminal domain (BET) protein inhibitors as potent radiosensitizers in DMG cells. Genetic and pharmacologic inhibition of BET bromodomain activity reduced DMG cell proliferation and enhanced radiation-induced DNA damage by inhibiting DNA repair pathways. RNA-Seq and the CUT&RUN (cleavage under targets and release using nuclease) analysis showed that BET bromodomain inhibitors regulated the expression of DNA repair genes mediated by H3K27 acetylation at enhancers. BET bromodomain inhibitors enhanced DMG radiation response in patient-derived xenografts as well as genetically engineered mouse models. Together, our results highlight BET bromodomain inhibitors as potential radiosensitizer and provide a rationale for developing combination therapy with radiation for the treatment of DMG.

Original language	English (US)
Article number	e174794
Journal	Journal of Clinical Investigation
Volume	134
Issue number	13
DOIs	https://doi.org/10.1172/JCI174794
State	Published - Jul 1 2024

Funding

We would like to thank the Rally Foundation for Childhood Cancer Research, Pediatric Cancer Research Foundation, Cure Starts Now Foundation, and Matthew Larson Foundation for funding. ZZ is supported by NIH grant R01NS132344. OJB is supported by NIH grants R01CA197313 and R01CA258636. JW is supported by JSPS Overseas Research Fellowships. RH is supported by NIH grant R01NS126513. We would like to acknowledge the Northwestern University High Throughput Analysis Laboratory, Mouse Histology and Phenotypic Core, and NUSeq Core facilities. The initial drug screen was supported by a developmental research project awarded to OJB, RH, and MRC through the NU Brain SPORE award mechanism (5P50CA221747). We would like to thank the Rally Foundation for Childhood Cancer Research, Pediatric Cancer Research Foundation, Cure Starts Now Foundation, and Matthew Larson Foundation for funding. ZZ is supported by NIH grant R01NS132344. OJB is supported by NIH grants R01CA197313 and R01CA258636. JW is supported by JSPS Overseas Research Fellowships. RH is supported by NIH grant R01NS126513. We would like to acknowledge the North-western University High Throughput Analysis Laboratory, Mouse Histology and Phenotypic Core, and NUSeq Core facilities. The initial drug screen was supported by a developmental research project awarded to OJB, RH, and MRC through the NU Brain SPORE award mechanism (5P50CA221747).

ASJC Scopus subject areas

General Medicine

UN SDGs

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

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10.1172/JCI174794

Cite this

Watanabe, J., Clutter, M. R., Gullette, M. J., Sasaki, T., Uchida, E., Kaur, S., Mo, Y., Abe, K., Ishi, Y., Takata, N., Natsumeda, M., Gadd, S., Zhang, Z., Becher, O. J., & Hashizume, R. (2024). BET bromodomain inhibition potentiates radiosensitivity in models of H3K27-altered diffuse midline glioma. Journal of Clinical Investigation, 134(13), Article e174794. https://doi.org/10.1172/JCI174794

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title = "BET bromodomain inhibition potentiates radiosensitivity in models of H3K27-altered diffuse midline glioma",

abstract = "Diffuse midline glioma (DMG) H3K27-altered is one of the most malignant childhood cancers. Radiation therapy remains the only effective treatment yet provides a 5-year survival rate of only 1%. Several clinical trials have attempted to enhance radiation antitumor activity using radiosensitizing agents, although none have been successful. Given this, there is a critical need for identifying effective therapeutics to enhance radiation sensitivity for the treatment of DMG. Using high-throughput radiosensitivity screening, we identified bromo- and extraterminal domain (BET) protein inhibitors as potent radiosensitizers in DMG cells. Genetic and pharmacologic inhibition of BET bromodomain activity reduced DMG cell proliferation and enhanced radiation-induced DNA damage by inhibiting DNA repair pathways. RNA-Seq and the CUT&RUN (cleavage under targets and release using nuclease) analysis showed that BET bromodomain inhibitors regulated the expression of DNA repair genes mediated by H3K27 acetylation at enhancers. BET bromodomain inhibitors enhanced DMG radiation response in patient-derived xenografts as well as genetically engineered mouse models. Together, our results highlight BET bromodomain inhibitors as potential radiosensitizer and provide a rationale for developing combination therapy with radiation for the treatment of DMG.",

author = "Jun Watanabe and Clutter, {Matthew R.} and Gullette, {Michael J.} and Takahiro Sasaki and Eita Uchida and Savneet Kaur and Yan Mo and Kouki Abe and Yukitomo Ishi and Nozomu Takata and Manabu Natsumeda and Samantha Gadd and Zhiguo Zhang and Becher, {Oren J.} and Rintaro Hashizume",

note = "Publisher Copyright: Copyright: {\textcopyright} 2024, Watanabe et al.",

year = "2024",

month = jul,

day = "1",

doi = "10.1172/JCI174794",

language = "English (US)",

volume = "134",

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Watanabe, J, Clutter, MR, Gullette, MJ, Sasaki, T, Uchida, E, Kaur, S, Mo, Y, Abe, K, Ishi, Y, Takata, N, Natsumeda, M, Gadd, S, Zhang, Z, Becher, OJ & Hashizume, R 2024, 'BET bromodomain inhibition potentiates radiosensitivity in models of H3K27-altered diffuse midline glioma', Journal of Clinical Investigation, vol. 134, no. 13, e174794. https://doi.org/10.1172/JCI174794

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T1 - BET bromodomain inhibition potentiates radiosensitivity in models of H3K27-altered diffuse midline glioma

AU - Watanabe, Jun

AU - Clutter, Matthew R.

AU - Gullette, Michael J.

AU - Sasaki, Takahiro

AU - Uchida, Eita

AU - Kaur, Savneet

AU - Mo, Yan

AU - Abe, Kouki

AU - Ishi, Yukitomo

AU - Takata, Nozomu

AU - Natsumeda, Manabu

AU - Gadd, Samantha

AU - Zhang, Zhiguo

AU - Becher, Oren J.

AU - Hashizume, Rintaro

PY - 2024/7/1

Y1 - 2024/7/1

N2 - Diffuse midline glioma (DMG) H3K27-altered is one of the most malignant childhood cancers. Radiation therapy remains the only effective treatment yet provides a 5-year survival rate of only 1%. Several clinical trials have attempted to enhance radiation antitumor activity using radiosensitizing agents, although none have been successful. Given this, there is a critical need for identifying effective therapeutics to enhance radiation sensitivity for the treatment of DMG. Using high-throughput radiosensitivity screening, we identified bromo- and extraterminal domain (BET) protein inhibitors as potent radiosensitizers in DMG cells. Genetic and pharmacologic inhibition of BET bromodomain activity reduced DMG cell proliferation and enhanced radiation-induced DNA damage by inhibiting DNA repair pathways. RNA-Seq and the CUT&RUN (cleavage under targets and release using nuclease) analysis showed that BET bromodomain inhibitors regulated the expression of DNA repair genes mediated by H3K27 acetylation at enhancers. BET bromodomain inhibitors enhanced DMG radiation response in patient-derived xenografts as well as genetically engineered mouse models. Together, our results highlight BET bromodomain inhibitors as potential radiosensitizer and provide a rationale for developing combination therapy with radiation for the treatment of DMG.

AB - Diffuse midline glioma (DMG) H3K27-altered is one of the most malignant childhood cancers. Radiation therapy remains the only effective treatment yet provides a 5-year survival rate of only 1%. Several clinical trials have attempted to enhance radiation antitumor activity using radiosensitizing agents, although none have been successful. Given this, there is a critical need for identifying effective therapeutics to enhance radiation sensitivity for the treatment of DMG. Using high-throughput radiosensitivity screening, we identified bromo- and extraterminal domain (BET) protein inhibitors as potent radiosensitizers in DMG cells. Genetic and pharmacologic inhibition of BET bromodomain activity reduced DMG cell proliferation and enhanced radiation-induced DNA damage by inhibiting DNA repair pathways. RNA-Seq and the CUT&RUN (cleavage under targets and release using nuclease) analysis showed that BET bromodomain inhibitors regulated the expression of DNA repair genes mediated by H3K27 acetylation at enhancers. BET bromodomain inhibitors enhanced DMG radiation response in patient-derived xenografts as well as genetically engineered mouse models. Together, our results highlight BET bromodomain inhibitors as potential radiosensitizer and provide a rationale for developing combination therapy with radiation for the treatment of DMG.

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BET bromodomain inhibition potentiates radiosensitivity in models of H3K27-altered diffuse midline glioma

Abstract

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UN SDGs

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