PLK1 as a cooperating partner for BCL2-mediated antiapoptotic program in leukemia.

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• Deregulation of BCL2 family proteins is critical in leukemia pathogenesis.
• Pharmacological inhibition of BCL2 proteins is a key therapeutic strategy.
• Primary and acquired resistance to BCL2 inhibitors compromises treatment efficacy.

Purpose of the Study:

• To develop a predictive model for venetoclax sensitivity in T-cell acute lymphoblastic leukemia (T-ALL).
• To identify novel therapeutic targets that cooperate with BCL2-mediated antiapoptotic pathways in T-ALL.

Main Methods:

• A deep tabular learning algorithm was used to predict venetoclax sensitivity in T-ALL patient samples.
• Phosphoproteomics and high-throughput kinase screening were employed to identify cooperating targets.
• Combination therapy studies involved venetoclax with PLK1 inhibitors or PLK1 knockdown in T-ALL models.

Main Results:

• Polo-like kinase 1 (PLK1) was identified as a cooperating partner in BCL2-mediated antiapoptosis.
• Concurrent venetoclax and PLK1 inhibition demonstrated enhanced therapeutic effects in T-ALL cell lines, xenografts, and mice.
• PLK1 attenuation increased BCL2 inhibitor sensitivity via upregulation of BCL2L13 and PMAIP1.

Conclusions:

• T-ALL exhibits a dependency on PLK1, suggesting it as a viable therapeutic target.
• Combining PLK1 inhibition with BCL2 inhibitors offers a promising strategy to overcome venetoclax resistance in T-ALL.
• A regulatory mechanism involving PLK1, BCL2L13, and PMAIP1 in T-ALL apoptosis was elucidated.