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A step ahead of cancer cells: Important insights into resistance building

BRD4 inhibitors are among the most promising new agents in cancer therapy that are currently evaluated in clinical trials. In a study published in NATURE, a team of researchers at the Research Institute of Molecular Pathology (IMP) and in Vienna reveals how leukemia cells can evade the deadly effects of BRD4 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 turns out to be a major challenge for modern medicine. Searching for new ways to attack , the laboratory of Johannes Zuber at the IMP in Vienna uses so-called functional genetic screens to probe vulnerabilities of in a systematic and unbiased way. The major goal is to find genes that particularly depend on, and then exploit these “Achilles’ heels” for the development of targeted therapies. In a first study applying this technology, Zuber and his former colleagues at Cold Spring Harbor Laboratory (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. This discovery sparked a lot of excitement about BRD4 as a new target for leukemia therapy, and only four years later several BRD4 inhibitors have entered clinical trials, some of which have already reported promising results.

Resistance To New Cancer Therapies Is Often Poorly Understood

Despite this rapid advance, doctors and researchers still do not understand why some cancers are so sensitive to BRD4 inhibitors while others remain resistant. “After discovering a new Achilles’ heel, we often have no clue why cancer cells depend on a certain gene, although this knowledge would be crucial for developing targeted therapies and selecting the right patients”, explains Zuber. In the case of BRD4, finding an answer to this question turned out to be particularly challenging. To tackle this problem, Zuber and his group at the IMP teamed up with previous co-workers in the U.S. and scientists at Boehringer Ingelheim in Vienna led by Norbert Kraut to characterize sensitive and resistant cancer cells. Results from this work have been published in Nature and reveal a fascinating new mechanism how leukemia cells evade their dependency on BRD4.

Image of cancer cell with keys
Targeted agents are thought to be keys to better Cancer Therapy. Cancer cells can adapt to targeted therapies, so the best key combination can change over time.
Credit: Research Institute of Molecular Pathology (IMP)