PLK1: a promising and previously unexplored target in double-hit lymphoma

Area of Science:

• Oncology
• Molecular Biology
• Hematology

Background:

• Targeted therapies are crucial for cancers lacking specific oncogenic drivers or relying on multiple progression mechanisms.
• Combinations of targeted therapies are essential to overcome resistance in various cancers.
• Double-hit lymphoma (DHL) is an aggressive B cell lymphoma subtype often lacking single targetable kinases.

Purpose of the Study:

• To identify novel therapeutic targets in double-hit lymphoma (DHL).
• To evaluate the efficacy of polo-like kinase-1 (PLK1) inhibition in DHL models.
• To assess PLK1 as a prognostic marker in DHL patients.

Main Methods:

• Kinase activity-profiling to identify key drivers in DHL.
• Assessment of PLK1 activity in relation to MYC expression and patient prognosis.
• Inhibition of PLK1 using volasertib, alone and in combination with venetoclax, in DHL models.

Main Results:

• PLK1 activity was identified as a significant driver in double-hit lymphoma (DHL).
• Increased PLK1 activity correlated with MYC expression and indicated a poor prognosis in DHL patients.
• PLK1 inhibition with volasertib demonstrated efficacy in DHL models, including patient-derived xenografts.

Conclusions:

• Polo-like kinase-1 (PLK1) is a promising prognostic marker for double-hit lymphoma (DHL).
• Targeting PLK1 with volasertib, alone or combined with venetoclax, offers a potential therapeutic strategy for DHL.
• PLK1 inhibition represents a viable therapeutic avenue for aggressive B cell lymphomas.