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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\n                  <jats:italic>BRD2<\/jats:italic>\n                  knockout synergized with PI3K pathway inhibitors in breast cancer cell lines, patient-derived organoids, and\n                  <jats:italic>in vivo<\/jats:italic>\n                  models.\n                  <jats:italic>BRD2<\/jats:italic>\n                  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\u2013PI3Ki 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.\n                <\/jats:p>","DOI":"10.64898\/2026.09.21.753236","type":"posted-content","created":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T22:25:10Z","timestamp":1790115910000},"source":"Crossref","is-referenced-by-count":0,"title":["MAPK signaling links BRD2 chromatin occupancy to PI3K\/AKT inhibitor sensitivity"],"prefix":"10.64898","author":[{"given":"Josefina","family":"Mendez","sequence":"first","affiliation":[{"name":"Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Bruno","sequence":"additional","affiliation":[{"name":"Department of Data Science, Dana-Farber Cancer Institute, Boston, Massachusetts, USA"},{"name":"Department of Biostatistics, Harvard T.H. 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