A dual mechanism of sensitivity to PLK4 inhibition by RP-1664 in neuroblastoma
A novel therapeutic strategy was recently proposed for high-risk neuroblastoma carrying copy number gain of the TRIM37 gene: centriole loss upon inhibition of polo-like kinase 4 (PLK4), while tolerated by normal cells, induces aberrant mitotic spindle formation and p53-dependent cell death in TRIM37-overexpressing cells. Interestingly, while full PLK4 inhibition causes centriole loss, partial inhibition is known to elevate centriole numbers. Here we show using a novel selective PLK4 inhibitor RP-1664 that both centriole loss and amplification contribute to hypersensitivity of neuroblastoma cells. Whereas inactivation of TRIM37 and TP53 rescues neuroblastoma cell death at higher concentrations of RP-1664, at lower doses cell death is TRIM37/TP53-independent. With CRISPR screens and live cell imaging we demonstrate that upon centriole amplification, neuroblastoma cells succumb to multipolar mitoses due to inability to cluster or inactivate supernumerary centrosomes. In vivo, RP-1664 shows robust efficacy in neuroblastoma xenografts at doses consistent with centriole amplification. STATEMENT OF SIGNIFICANCEHigh-risk neuroblastoma is associated with poor outcomes in pediatric patients and novel therapies need to be developed. We show that neuroblastoma cells are remarkably sensitive to PLK4 inhibitors due to a combination of two complementary mechanisms, supporting the evaluation of PLK4 inhibitors in clinical trials of high-risk neuroblastoma.