Posted: Wednesday, March 3, 2021
According to research presented in Nature Communications, combined therapy of MDM2 inhibitors plus BET inhibitors may result in significant antileukemia activity in patients with acute myeloid leukemia (AML). Each of the included treatments is known to be only partially effective as a monotherapy in this patient population, which is known often to retain TP53, the most commonly mutated gene across all cancers. TP53 produces the tumor-suppressing p53.
“Our research unexpectedly showed that like MDM2 inhibitors, BET inhibitors activate p53, but through a different pathway. BET inhibitors mute the power of a protein called BRD4, which we found is a p53 suppressor in AML,” noted Peter D. Adams, PhD, of Sanford Burnham Prebys Medical Discovery Institute in San Diego, in an institutional press release. “Between the two drugs, you end up with a ‘double whammy’ effect that fully unleashes the anticancer activity of p53.”
The in vitro session of the study included primary cancer cells from 15 patients with AML. When administered in conjunction, the BET inhibitor CPI203 and the MDM2 inhibitor nutlin-3 were found to be significantly more effective in these samples than either was in isolation. The study also included an in vivo session, which demonstrated that the combination resulted in improved anticancer activity in a mouse model with aggressive AML.
“This study illustrates that targeting BRD4 as part of a combination therapy holds promise for patients diagnosed with this very dangerous disease,” Dr. Adams commented.
Disclosure: For full disclosures of the study authors, visit nature.com.