Patients with TP53-mutant acute myeloid leukemia (AML) respond poorly to currently available therapies, including the combination of venetoclax and hypomethylating agents, which presents a major therapeutic challenge. A new potential therapeutic target, the epichaperome complex, is a protein network consisting of heat-shock proteins and co-chaperones found in many tumors that support the survival of cancer cells. Researchers led by Bing Carter, Ph.D., and Michael Andreeff, M.D., Ph.D., identified high levels of epichaperomes in TP53-mutant AML cells.
They found that targeting epichaperomes with the selective inhibitor PU-H71 had significant anti-leukemia effects in AML cells and stem cells with TP53 mutations but not in normal bone marrow stem cells. Importantly, they demonstrated that venetoclax selects for the outgrowth of TP53-mutant AML cells, while PU-H71 eliminates these cells and enhances venetoclax activity.