THE AURORA KINASE A (AURKA) INHIBITOR ALISERTIB ACTS SYNERGISTICALLY WITH A POLO-LIKE KINASE 4 (PLK4) INHIBITOR TO TARGET ATYPICAL TERATOID / RHABDOID TUMOR (AT/RT) CELLS

Previously, we observed that CRISPR/Cas9-induced mutations in the PLK4 gene, a critical regulator of centriole duplication, significantly impaired proliferation and survival of AT/RT cells. We established that PLK4 is overexpressed in AT/RT and inhibiting PLK4 resulted in impaired proliferation, survival, migration and invasion. It also induced polyploidy increasing AT/RT susceptibility to DNA-damaging drugs. The inhibition of AURKA, also overexpressed in AT/RT by alisertib, is currently in phase II clinical trial for the treatment of rhabdoid tumors (RT) (NCT02114229). We hypothesized that associating alisertib with a PLK4 inhibitor (PLK4i) would improve the efficacy of each drug. We tested association of alisertib with the PLK4i CFI-400945 in three RT cell lines (MON, BT-12 and BT-16). Multiple concentrations for each inhibitor alone and in combination were tested. PrestoBlue viability and MTT proliferation assays were performed. Median effect plots showed that CFI-400945 associated with alisertib significantly decreased the concentration of both inhibitors needed to affect proliferation and viability in all cell lines tested. While alisertib alone required 200-500nM and CFI-400945 alone required 3.000–6.000nM to inhibit 50% proliferation and viability (IC50), combination of the two drugs required only 10-40nM of alisertib (13–20 times less) and 5-10nM of CFI-400945 (over 500 times less) to produce the same effect (p-value<0.001 in at least two cell lines for each assay). The PLK4i acts synergistically with alisertib to target RT cells. This association can represent a novel, less toxic strategy to treat AT/RT. The Musella Foundation for Cancer Research.