Original story from the Max Planck Institute of Immunobiology and Epigenetics (Freiburg, Germany). Understanding the distinct roles of BET proteins could unlock a more targeted approach to cancer therapy. For over a decade, a class of drugs called ‘Bromo- and Extra-Terminal domain’ (BET) inhibitors has been tested in cancer trials with high expectations. The biology looked promising. Many cancers depend on oncogenes that BET proteins help activate, so blocking BET proteins should slow tumor growth. In the lab, it often did. In patients, results were mostly disappointing: limited responses, significant side effects, and no clear way to predict which tumors would respond at all. A new study from the Max Planck Institute of Immunobiology and Epigenetics (MPI-IE; Freiburg, Germany) now offers a possible explanation for why and points towards developing a more precise mode of therapy. Treating an entire protein family as a single target BET inhibitors were developed to block a shared domain that all BET proteins use to bind chromatin, the tightly packed complex of DNA and proteins in which genes are stored and regulated. Blocking chromatin binding seemed a reasonable strategy to silence the machinery that reads the oncogenes, hinging on the assumption that all BET proteins do roughly the same thing. A new study by the lab of Asifa Akhtar offers a more nuanced picture. Their work reveals that two key BET proteins from the family, BRD2 and BRD4, perform distinct roles at different stages in gene activation. BDR4 drives the step that most current therapies…
