Researchers studying the mechanism of action of BET inhibitors, drugs thought to be of promise in treating blood cancers such as leukemia and lymphoma, report discovering not only how these drugs kill cancer cells but also how tumor cells develop resistance to them. The study, “BET inhibition represses miR17-92 to drive BIM-initiated apoptosis of normal and transformed hematopoietic cells,” was published in Leukemia.
BET (bromodomain and extraterminal domain) proteins are key mediators of gene expression, controlling whether genes are transcribed and translated into such factors as proteins and RNA, or not. For this reason, BET proteins are seen as promising treatment targets for lymphoid and myeloid malignancies.
While BET inhibitors are known to be able to halt cancer growth, however, whether these drugs only pause such growth or effectively kill cancer cells is still unclear.
The scientists found that BET inhibitors mainly kill cancer cells through apoptosis, a process of programmed cell death. Moreover, for the drugs to successfully kill tumor cells, a protein called BIM, crucial for apoptosis, has to be present. Importantly, they also identified key mutations that would render cancer cells resistant to the drugs.
“We found that when apoptosis was impaired, for instance by loss of BIM, the BET inhibitors were no longer effective,” Dr. Zhen Xu, a postdoctoral researcher at the Walter and Eliza Hall Institute of Medical Research, in Australia, said in a news release. “This suggests that cancer cells that acquire mutations in genes that drive apoptosis will lose sensitivity to BET inhibitors and thus will be able to survive treatment, leading to disease relapse.”
Study authors believe their findings help both to further understanding into how BET inhibitors work, and to developing strategies to improve their effectiveness. “Understanding how the drugs work gives us the opportunity to investigate new treatments, for example by using combination therapies, or altering the dosage and timing of treatment to prevent drug resistance from emerging,” said Dr. Stefan Glaser, the study’s lead investigator.