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

Abstract

Inhibitors that target specific kinases or oncoproteins have become popular additions to or replacements for cytotoxic chemotherapies to treat many different types of cancer. However, many tumors lack a discernable target kinase and an amplified oncoprotein and/or rely on several cooperating mechanisms for progression. Thus, combinations of targeted therapies are essential for treating many cancers to avoid the rapid emergence of resistance. In this issue of the JCI, Ren et al. use an elegant kinase activity-profiling method and identify activity of the oncogene polo-like kinase-1 (PLK1) as an important driver of double-hit lymphoma (DHL), an aggressive subgroup of B cell lymphoma characterized by chromosomal translocations involving c-MYC and BCL2 or BCL6. Moreover, PLK1 activity was associated with MYC expression and poor prognosis in DHL patients. PLK1 inhibition with volasertib, alone and in combination with the BCL-2 inhibitor venetoclax, was efficacious in multiple DHL models, including mice harboring DHL patient-derived xenografts. Together, these data support PLK1 as a promising prognostic marker and therapeutic target for DHL.

Figure 1. PLK1 activity contributes to disease pathogenesis in DHL.

DHL is characterized by overactivity of both MYC and BCL-2 oncoproteins. MYC overactivity contributes to the development of cancer by increasing cell proliferation. Aberrant BCL-2 activity helps prevent apoptosis, and while not sufficient to cause cancer alone, can support metabolism and cell-cycle changes by other oncogenes. (A) In this issue, Ren et al. identify PLK1 as an important regulator of DHL. Specifically, PLK1 was shown to stabilize MCL1, a BCL-2 family member that is known to mediate resistance to the BCL-2 inhibitor venetoclax. Moreover, PLK1 interacts with MYC to form a feed-forward circuit in which PLK1 helps stabilize MYC and MYC activates further PLK1 transcription. (B) Ren et al. show that targeting PLK1 with volasertib destabilizes MYC and MCL1 in DHL and may be a way to indirectly target MYC, which is currently considered “undruggable.”