Epichaperome inhibition targets TP53-mutant AML and AML stem/progenitor cells

Area of Science:

• Oncology
• Molecular Biology
• Hematology

Background:

• TP53-mutant acute myeloid leukemia (AML) presents a significant therapeutic challenge.
• Epichaperomes, complexes involving heat shock protein 90 (HSP90), are crucial for oncogenic protein stability in malignant cells, including mutant p53.
• HSP90 inhibitors show promise in AML, with epichaperomes identified in TP53-mutant AML cells and stem/progenitor cells.

Purpose of the Study:

• To investigate the therapeutic potential of targeting epichaperomes with PU-H71 in TP53-mutant AML.
• To assess the specificity of PU-H71 for malignant cells versus healthy hematopoietic stem and progenitor cells.
• To evaluate the synergistic effects of PU-H71 with venetoclax in TP53-mutant AML.

Main Methods:

• High-throughput drug screening to identify HSP90 inhibitors.
• Detection of epichaperomes in AML and healthy bone marrow (BM) cells.
• In vitro and in vivo studies using PU-H71 in TP53-mutant AML models (xenografts and patient-derived).
• Assessment of molecular targets and combination therapy with venetoclax.

Main Results:

• PU-H71 effectively killed TP53-mutant AML cells and stem/progenitor cells by inducing apoptosis.
• PU-H71 demonstrated minimal toxicity to healthy human BM CD34+ cells and murine hematopoiesis.
• PU-H71 synergized with venetoclax, enhancing cell killing and preventing the outgrowth of resistant TP53-mutant clones.

Conclusions:

• Epichaperome inhibition is a viable strategy for targeting TP53-mutant AML and its stem/progenitor cells.
• PU-H71 shows therapeutic potential in TP53-mutant AML, with favorable safety and synergistic activity with venetoclax.
• Targeting epichaperomes warrants clinical evaluation for the treatment of TP53-mutant AML.