Researchers from Walter and Eliza Hall Institute (WEHI; VIC, Australia) have demonstrated that a promising new class of anticancer drugs, Bromodomain and Extra-Terminal motif (BET) inhibitors, may reduce tumor growth by driving tumor cell apoptosis. While BET inhibitors have been successfully employed in the treatment of blood cancers, it has, until now, been unclear by which mechanism they reduce tumor growth.
BET inhibitors have previous been demonstrated to halt tumor growth in blood cancers such as leukemias and lymphomas. However, it has been unclear whether these anticancer drugs kill cancer cells or simply pause cell growth. In this new study, published in Leukemia, researchers indentified the mechanism by which BET inhibitors may stop tumor growth, and also by which cancers can become resistant to this treatment.
In experiments on lymphoma and myeloid leukemia cells, the team observed that BET inhibitors principally act to kill cancer cells via apoptosis. They further demonstrated that in order for successful apoptosis to occur, the presence of another protein termed BIM is also necessary.
“We found that when apoptosis was impaired, for instance by loss of BIM, the BET inhibitors were no longer effective,” explained lead author, Zhen Xu (WEHI). “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.”
The team hope that an understanding of the mechanism of action of these drugs could help in the development of novel anticancer treatment approaches. Senior author Stefan Glaser (WEHI) commented: “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.”
Sources: Xu Z, Sharp PP, Yao Y et al. BET inhibition represses miR17-92 to drive BIM-initiated apoptosis of normal and transformed hematopoietic cells. Leukemia. doi:10.1038/leu.2016.52 (2016) (Epub ahead of print); WEHI press release