The effects of Aurora Kinase inhibition on thyroid cancer growth and sensitivity to MAPK-directed therapies

Background: Advanced papillary thyroid cancer (PTC) and anaplastic (ATC) are the leading causes of endocrine death. Mutations in MAP kinase (MAPK) pathway common PTC ATC. Recently, combination dabrafenib (BRAFi) trametinib (MEKi) was approved for treatment BRAF-mutant However, combined BRAF/ MEK inhibition is rarely curative ATC patients has had limited responses PTC. Here, we identify an induction Aurora Kinase B (AURKB) response to MEKi cells that resistant BRAF/MEK inhibition. We therefore hypothesize AURKB will sensitize MAPK-directed therapies. Materials Methods: Cell signaling were assessed using western blots cell growth measured by ViCell, Cell-Titer Glo, or IncuCyte ZOOM Live Imaging. Long-term clonogenic assays. Apoptosis cleaved caspase 3/7 Synergy calculated Combination Index (CI). RNA-sequencing data analyzed BioJupies. Results: In a panel lines, BRAFi/MEKi blocks MAPK signaling, indicated 83%–100% pERK (p < 0.03), variably affects PI3 K/AKT signaling. Combined prevents inhibits viability 43–80%. Calculation CI values indicates BRAF synergistically majority lines (CI value<0.75), but not those harboring PIK3CA mutations. To potential mechanisms mediating resistance, treated four sensitive with 48 hrs then performed RNA-sequencing. identified upregulation = 3.22 × 10−6) downregulation 6.43 10−10). further found barasertib (AURKi) enhances compared BRAFi/MEKi, decreasing 61–91% (0.0002 p 0.04). Finally, evaluated apoptosis inhibiting different nodes along AURKi. BRAF, ERK, significant effect on apoptosis, 73–81% 0.0001) increasing 1.4 9.3-fold. Conclusions: subset lines. some remain this upregulate Further, multiple (BRAF, MEK, ERK) AURKi significantly decreases increases suggesting promising target overcome resistance MAPK-pathway. No conflict interest.