Precision Targeting of BFL-1/A1 and an ATM Co-dependency in Human Cancer

Area of Science:

• Oncology
• Molecular Biology
• Drug Discovery

Background:

• Cancer cells utilize anti-apoptotic proteins like BCL-2, MCL-1, and BFL-1/A1 for survival.
• Targeting these proteins is crucial for overcoming cancer treatment resistance.
• BFL-1/A1 remains an undrugged target despite its oncogenic role.

Purpose of the Study:

• To engineer a functionally selective and cell-permeable BFL-1/A1 inhibitor.
• To identify BFL-1/A1 co-dependencies for combination therapies.
• To validate combination treatments for overcoming apoptotic resistance in cancer.

Main Methods:

• Development of stapled peptide design principles for BFL-1/A1 inhibition.
• Genome-scale CRISPR-Cas9 screening to identify cancer co-dependencies.
• In vitro validation of BFL-1/A1 and ATM inhibitor co-treatment.

Main Results:

• A novel, cell-permeable BFL-1/A1 inhibitor was engineered.
• Ataxia-telangiectasia-mutated (ATM) kinase was identified as a BFL-1/A1 co-dependency in acute myeloid leukemia (AML).
• Co-treatment with BFL-1/A1 and ATM inhibitors demonstrated synergistic effects in overcoming apoptotic resistance.

Conclusions:

• Targeting BFL-1/A1 with engineered inhibitors is a viable strategy for cancer therapy.
• ATM kinase is a key co-dependency that sensitizes cancer cells to BFL-1/A1 inhibition.
• Combination therapy with BFL-1/A1 and ATM inhibitors shows promise for treating resistant cancers, particularly AML.