BRD4 Inhibitors, AML, Enhancers; Cancer Vulnerability to BRD4 Inhibition Enhanced by Weak WNT Signaling; Loss of PRC2 Complex Increases Cancer Resistance to BRD4 Inhibition

BRD4 inhibitors are among the most promising new agents in cancer therapy and they are currently being evaluated in clinical trials. BRD4 is a member of the BET (bromo- and extra-terminal (BET) family of proteins: BRD2 (bromodomain-containing protein 2), BRD3 (bromodomain-containing protein 3), and BRD4 (bromodomain-containing protein 4). In a study published online on September 14, 2015 in Nature, a team of researchers at the Research Institute of Molecular Pathology (IMP) and Boehringer Ingelheim. both in Vienna, Austria reveals how leukemia cells can evade the deadly effects of BRD4 inhibition. The article is titled “Transcriptional Plasticity Promotes Primary and Acquired Resistance to BET Inhibition.” Understanding this adaptation process could aid the development of sequential therapies to outsmart resistant leukemias. Over the past years, scientists have drawn an almost complete map of mutations in cancer. However, translating complex genetic knowledge into effective cancer therapies turns out to be a major challenge for modern medicine. Searching for new ways to attack cancer cells, the laboratory of Dr. Johannes Zuber at the IMP in Vienna uses so-called functional genetic screens to probe vulnerabilities of cancer cells in a systematic and unbiased way. The major goal is to find genes that cancer cells particularly depend on, and then exploit these “Achilles’ heels” for the development of targeted therapies. In a first study applying this technology, Dr. Zuber and his former colleagues at Cold Spring Harbor Laboratory (CSHL) (New York) in 2011 found that the gene BRD4 is such an “Achilles’ heel” in acute myeloid leukemia (AML), an aggressive form of blood cancer.
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