MAPK signaling links BRD2 chromatin occupancy to PI3K/AKT inhibitor sensitivity

Abstract

Bromodomain and extra-terminal (BET) proteins, BRD2, BRD3, BRD4, and BRDT, couple histone acetylation to transcription by recruiting elongation and transcription factor complexes to chromatin. Although BET proteins are promising therapeutic targets, the functions of individual family members remain incompletely understood. We identify BRD2 as a co-targetable vulnerability with PI3K/AKT inhibition in breast cancer. Pan-BET inhibition and BRD2 knockout synergized with PI3K pathway inhibitors in breast cancer cell lines, patient-derived organoids, and in vivo models. BRD2 knockout impaired proliferation of triple-negative breast cancer cells and upregulated signaling and stress-response pathways, including the DNA damage response. Mechanistically, BRD2 is phosphorylated at Ser37 by the mitogen- and stress-activated kinases MSK and RSK, and Ser37 phosphorylation is required for chromatin binding and reader function. Finally, mechanistic digital twin modeling identified BETi-PI3Ki regimens that maintained efficacy while reducing drug exposure. Together, these findings identify BRD2 as a phosphorylation-dependent, co-targetable vulnerability in PI3K-inhibited breast cancer.

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BibTeX RIS

BibTeX

@misc{mendez2026mapk,
  title = {{MAPK signaling links BRD2 chromatin occupancy to PI3K/AKT inhibitor sensitivity}},
  author = {J. Mendez and S. Bruno and A. Indeglia and T. Khan and I. Ranieri and J. Wang and J. Hogstrom and A. Hillis and J. Lee and J. Clohessy and T. Muranen and W. Wei and F. Michor and K. Cichowski and A. Toker},
  howpublished = {bioRxiv},
  year = {2026},
  month = sep,
  doi = {10.64898/2026.09.21.753236},
  url = {https://www.biorxiv.org/content/10.64898/2026.09.21.753236v1},
  note = {CC BY-NC-ND},
}

RIS

TY  - UNPB
TI  - MAPK signaling links BRD2 chromatin occupancy to PI3K/AKT inhibitor sensitivity
AU  - J. Mendez
AU  - S. Bruno
AU  - A. Indeglia
AU  - T. Khan
AU  - I. Ranieri
AU  - J. Wang
AU  - J. Hogstrom
AU  - A. Hillis
AU  - J. Lee
AU  - J. Clohessy
AU  - T. Muranen
AU  - W. Wei
AU  - F. Michor
AU  - K. Cichowski
AU  - A. Toker
PY  - 2026
DA  - 2026/09/21
PB  - bioRxiv
DO  - 10.64898/2026.09.21.753236
UR  - https://www.biorxiv.org/content/10.64898/2026.09.21.753236v1
AB  - Bromodomain and extra-terminal (BET) proteins, BRD2, BRD3, BRD4, and BRDT, couple histone acetylation to transcription by recruiting elongation and transcription factor complexes to chromatin. Although BET proteins are promising therapeutic targets, the functions of individual family members remain incompletely understood. We identify BRD2 as a co-targetable vulnerability with PI3K/AKT inhibition in breast cancer. Pan-BET inhibition and BRD2 knockout synergized with PI3K pathway inhibitors in breast cancer cell lines, patient-derived organoids, and in vivo models. BRD2 knockout impaired proliferation of triple-negative breast cancer cells and upregulated signaling and stress-response pathways, including the DNA damage response. Mechanistically, BRD2 is phosphorylated at Ser37 by the mitogen- and stress-activated kinases MSK and RSK, and Ser37 phosphorylation is required for chromatin binding and reader function. Finally, mechanistic digital twin modeling identified BETi-PI3Ki regimens that maintained efficacy while reducing drug exposure. Together, these findings identify BRD2 as a phosphorylation-dependent, co-targetable vulnerability in PI3K-inhibited breast cancer.
ER  -

Abstract

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