Acquired resistance to ABT-737 in lymphoma cells that up-regulate MCL-1 and BFL-1

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• ABT-737 is a BCL-2 antagonist in clinical trials (as ABT-263) for cancer treatment.
• Acquired drug resistance is a significant challenge in cancer therapy.
• Understanding resistance mechanisms is crucial for improving treatment efficacy.

Purpose of the Study:

• To investigate the mechanisms of acquired resistance to the BCL-2 inhibitor ABT-737 in lymphoma cell lines.
• To identify potential strategies to overcome ABT-737 resistance.

Main Methods:

• Derived ABT-737-resistant lymphoma cell lines (OCI-Ly1, SU-DHL-4) through long-term drug exposure.
• Analyzed protein and transcript levels of BCL-2 family members (BCL-2, BFL-1, MCL-1, BIM).
• Assessed drug binding and sensitivity after modulating MCL-1 levels using small molecules and shRNA.

Main Results:

• Resistance was mitochondrial, not due to impaired drug binding to BCL-2.
• Resistant cells exhibited increased levels of antiapoptotic BFL-1 and/or MCL-1 proteins.
• Proapoptotic BIM was sequestered by BFL-1/MCL-1 in resistant cells, despite displacement from BCL-2.
• Targeting MCL-1 with flavopiridol, PHA 767491, or shRNA restored sensitivity to ABT-737.
• MCL-1 and BFL-1 were upregulated at both transcript and protein levels, with a dynamic increase upon ABT-737 treatment.

Conclusions:

• Acquired resistance to ABT-737 involves upregulation of MCL-1 and/or BFL-1, which sequester BIM.
• Targeting MCL-1 resensitizes resistant cells to ABT-737, offering a therapeutic strategy.
• Dynamic transcriptional upregulation of antiapoptotic proteins suggests a novel communication pathway between drug action and nuclear transcription.