Potent synthetic lethality between PLK1 and EYA family inhibitors in tumors of the central and peripheral nervous systems.

The Eyes Absent family of protein phosphatases (EYA1-4) is aberrantly expressed and tumor-promoting across many devastating cancers of neurological origin affecting both children and adults. It has recently been demonstrated that EYA1 and EYA4 promote tumor cell survival by increasing the active pool of Polo-like kinase 1 (PLK1) molecules. This discovery provides a rationale for the therapeutic combination of EYA inhibitors with direct, ATP-competitive PLK1 inhibitors. Here, we demonstrate potent loss of cell viability in response to combined EYA and PLK1 inhibition in cancer cell lines that overexpress EYA1 and/or EYA4, including in neuroblastoma and glioblastoma models. We identify decreases in PLK1 activity and RAD51 focus formation and increases in mitotic arrest and cell death as mechanistic contributors to combination sensitivity. Combined EYA and PLK1 inhibition is also effective in glioblastoma stem cell models that overexpress EYA1/EYA4 and specifically targets the cancer stem cell state. Finally, through multiomic correlational analysis, we identify high levels of the NuRD complex and SOX9 as contributors to combination treatment sensitivity. Overall, this work identifies a novel synthetic-lethal combination therapy with potential utility across a wide range of neurological cancers.