Combined Inhibition of Polo-Like Kinase-1 and Wee1 as a New Therapeutic Strategy to Induce Apoptotic Cell Death in Neoplastic Mast Cells

Simple Summary Systemic Mastocytosis (SM) is a rare disease resulting from a clonal proliferation of mast cells. Despite the rarity of the disease, its advanced forms remain a hard core to manage in clinical practice. At this time, there are few therapeutic options available, such as midostaurin and avapritinib, hence the need to perform a deeper investigation of the pathogenetic mechanisms involved in the development of the most aggressive forms of the disease, in order to provide further tools for the therapeutic management of this critical subset of patients. In this study, we aimed to identify new biological players involved in the pathogenesis of SM, and to evaluate their role as potential therapeutic targets. Our results identify, for the first time, two druggable markers of aggressiveness of the disease: Aurora kinase A and Polo-like kinase 1. Inhibition of these two ser/thr kinases, alone or together with Wee1, induces apoptotic cell death in SM cell lines; therefore, it appears an attractive therapeutic strategy to kill neoplastic MCs. Repurposing Polo-like kinase 1 or Aurora kinase A +/- Wee1 inhibitors in advanced clinical developments for other indications is a therapeutic strategy worthy of being explored, to attempt to improve the outcome of patients with advanced SM. Systemic mastocytosis (SM) is due to the pathologic accumulation of neoplastic mast cells in one or more extracutaneous organ(s). Although midostaurin, a multikinase inhibitor active against both wild-type and D816V-mutated KIT, improves organ damage and symptoms, a proportion of patients relapse or have resistant disease. It is well known that Aurora kinase A (AKA) over-expression promotes tumorigenesis, but its role in the pathogenesis of systemic mastocytosis (SM) has not yet been investigated. Evidence from the literature suggests that AKA may confer cancer cell chemo-resistance, inhibit p53, and enhance Polo-like kinase 1 (Plk1), CDK1, and cyclin B1 to promote cell cycle progression. In this study, we aimed to investigate the pathogenetic role of AKA and Plk1 in the advanced forms of SM. We demonstrate here, for the first time, that SM cell lines display hyper-phosphorylated AKA and Plk1. Danusertib (Aurora kinase inhibitor) and volasertib (Plk1 inhibitor) inhibited growth and induced apoptotic cell death in HMC-1.1 and -1.2 cells. Their growth-inhibitory effects were associated with cell cycle arrest and the activation of apoptosis. Cell cycle arrest was associated with increased levels of phospho-Wee1. Wee1 inhibition by MK1775 after 24 h treatment with danusertib or volasertib, when cells were arrested in G2 phase and Wee1, was overexpressed and hyper-activated, resulting in a significantly higher rate of apoptosis than that obtained from concomitant treatment with danusertib or volasertib + MK1775 for 48 h. In conclusion, Plk1 and AKA, alone or together with Wee1, are attractive therapeutic targets in neoplastic MCs. Repurposing Plk1 or AKA +/- Wee1 inhibitors in advanced clinical development for other indications is a therapeutic strategy worthy of being explored, in order to improve the outcome of patients with advanced SM.

Automated summary

This study aimed to identify new therapeutic targets in the pathogenesis of systemic mastocytosis (SM). The results identified Aurora kinase A and Polo-like kinase 1 as potential targets for SM treatment. Inhibiting these kinases can induce apoptotic cell death in SM cell lines, suggesting it as an attractive therapeutic strategy. Further clinical development of inhibitors for these kinases could improve the outcome of patients with advanced SM.