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

Bromodomain and extra-terminal proteins, including BRD2, BRD3, BRD4, and BRDT, play a crucial role in histone acetylation and transcription by recruiting elongation and transcription factor complexes to chromatin. The individual functions of these BET proteins are still not fully understood, but researchers have now identified BRD2 as a co-targetable vulnerability in breast cancer when combined with PI3K/AKT inhibition.

When pan-BET inhibition and BRD2 knockout are used together with PI3K pathway inhibitors, they show synergistic effects on breast cancer cell lines, patient-derived organoids, and in vivo models. This means that the combination treatment is more effective than using either therapy alone.

Interestingly, BRD2 knockout impairs the proliferation of triple-negative breast cancer cells and activates signaling and stress-response pathways, such as the DNA damage response. The mechanism behind this lies in the phosphorylation of BRD2 at Ser37 by the mitogen- and stress-activated kinases MSK and RSK. This phosphorylation is critical for BRD2's chromatin binding and reader function.

To further understand the potential of this combination therapy, the researchers employed mechanistic digital twin modeling. This modeling identified BET inhibitor and PI3K inhibitor regimens that maintain efficacy while reducing drug exposure. In summary, these findings highlight BRD2 as a phosphorylation-dependent, co-targetable vulnerability in breast cancer treated with PI3K inhibitors.