The Novel Plk Inhibitor Volasertib Overcomes Cytarabine Resistance in Acute Myeloid Leukemia
Authors: Fu Shuang , Kelly Kevin R. , Espitia Claudia M. , Han Yingchun , Carraway Hetty E. , Advani Anjali S. , Maciejewski Jaroslaw P. , Sekeres Mikkael A. , Steffan Nawrocki T. , Carew Jennifer S. 
Published: October 2019

Abstract
Drug resistance is a major cause of treatment failure for patients with acute myeloid leukemia (AML) and novel approaches that circumvent or overcome resistance mechanisms are critically needed. Polo-like kinase 1 (PLK1) is a serine/threonine kinase that plays an important role in regulating cell cycle progression in M phase. It is overexpressed in a broad range of solid and hematological malignancies. Volasertib (BI 6727) is a novel PLK inhibitor that is currently under investigation in a Phase III clinical trial for patients with AML. Despite its reported clinical anti-AML activity, the efficacy and pharmacodynamics (PD) of volasertib have not been rigorously investigated in AML models in the preclinical setting. Here, we studied the activity and PD effects of volasertib in a panel of human AML cell lines and primary patient specimens. Low nanomolar concentrations of volasertib potently disrupted the viability and clonogenic survival of AML cells. Notably, the specific cytogenetic background of individual cell lines did not significantly impact cellular sensitivity to volasertib. Similarly, primary AML blasts from patients demonstrated ex vivo sensitivity to volasertib regardless of their cytogenetic and molecular features or prior treatment history. This in vitro data set is in line with recent Phase II clinical data in AML patients showing efficacy of volasertib across all cytogenetic risk categories. Volasertib triggered caspase-dependent apoptosis in AML cells in a manner that was preceded by disruption of the spindle assembly checkpoint. Notably, analysis of the activity of volasertib in three different paired cytarabine-sensitive and cytarabine-resistant AML cell line models revealed that volasertib retained its ability to diminish viability and stimulate apoptosis in cells with three log-fold increased cytarabine resistance. These findings suggest that volasertib may be effective for patients that have relapsed or are refractory to cytarabine-based regimens. Combination studies showed that volasertib and cytarabine yielded additive effects in cytarabine-sensitive cells. Gene expression profiling studies demonstrated that the chemokine CXCL10 was the most significantly upregulated gene following short-term treatment with low concentrations of volasertib. Subsequent qRT-PCR and ELISA experiments confirmed drug-induced CXCL10 expression and elevated CXCL10 secretion by AML cells. To our knowledge, this is the first report linking PLK1 inhibition to alterations in CXCL10 expression and secretion. We are currently investigating the specific contribution of CXCL10 to the anti-leukemic activity of volasertib and are elucidating the molecular mechanisms that mediate this effect. Collectively, our findings demonstrate that inhibition of PLK1 with volasertib is a promising new strategy for the treatment of AML that is able to overcome cytarabine resistance.

Disclosures
No relevant conflicts of interest to declare.