Image courtesy of PNAS
Researchers say they have determined how BET inhibitors fight hematologic malignancies.
Previous studies showed that BET inhibitors are effective at halting tumor growth, but it wasn’t clear whether the drugs kill cancer cells outright or merely pause their growth.
The new study provides an answer and reveals potential ways in which cancer cells may develop resistance to BET inhibitors.
The findings have been published in Leukaemia.
Researchers tested the BET inhibitors JQ1 and IBET151 in a range of hematopoietic cancer cell lines (leukemias, lymphomas, and multiple myeloma) and in mice (with and without malignancy).
The team found that JQ1’s ability to kill cancer cells principally relies on the activation of BAX/BAK-dependent mitochondrial apoptosis. They said this is largely triggered by upregulation of the protein BIM when BET inhibitors suppress miR-17-92, a post-transcriptional repressor of BIM expression.
“We found that when apoptosis was impaired—for instance, by loss of BIM—the BET inhibitors were no longer effective,” said study author Zhen Xu, PhD, of Walter and Eliza Hall Institute of Medical Research in Melbourne, Victoria, Australia.
“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 researchers also found that BET inhibitors could induce apoptosis in normal hematopoietic cells, particularly those of lymphoid origin. The team said this suggests the cells’ susceptibility to BET inhibitors did not arise from oncogenic transformation.
These findings could help researchers improve strategies for using BET inhibitors to treat cancers, according to study author Stefan Glaser, PhD, of the Walter and Eliza Hall Institute of Medical Research.
“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,” Dr Glaser said.
