Polo-like kinase inhibitor with radiation in betel-nuts related HNSCC in Taiwan

Abstract

Abstract Background The treatment of HNSCC in Taiwan is still very challenging. Betel-nuts chewing contributes to (1)strong iinvasion & angiogenesis; (2)poor response to chemotherapy, radiation, and EGFR inhibitors. In our previous studies, betel-nuts related TW2.6 (p53 defective mutation, p16 loss, BCL2+) was resistant to all traditional therapies. PI3K alpha inhibitor, AKT inhibitor, FGFR inhibitor, & VEGFR2/ PDGFR/FGFR or VEGFR2/c-MET/Axl triple blockage might be effective on TW2.6 and reverse treatment refractoriness, maybe through the inhibition of mesenchymal transformation & PI3K/AKT /mTOR signaling and the modulation of stemness & PD1/PDL1 pathway. PLK1 overexpression is prominent in HNSCC and related to poor prognosis. In our previous animal study for esophageal cancer, PLK1 inhibitor could induce p-Histone3 and synergize with radiation to further apoptosis.(Chen in Strahlenther Onkol 2016) Purpose We try to find out PLK1 inhibitor use for betel-nus related HNSCC. Methods Polo-like kinase 1 inhibitor(volasertib) was tested on TW2.6 to evaluate (1)in vitro drug sensitivity; (2)synergistic effects with some therapies by MTT, colony formation, flow cytometry, and western blotting. Results Combination of volasertib and radiation significantly enhanced radiation-induced death. The flow-cytometry revealed volasertib and radiation resulted in significant G2/M arrest. Western blotting also showed volasertib and radiation combination increased p-Histone3, p-CDK1, & cyclin B levels and apoptosis. TW2.6 was resistant to olaparib(PARP inhibitor), volasertib, or radiation alone; however, TW2.6 was sensitive again to (1)volasertib with radiation and (2)olaparib & volasertib. Conclusions PLK1 inhibition might be combined with radiation and other DNA damage response interventions in betel-nuts related HNSCC in Taiwan. Further predictive and dynamic biomarkers should be explored; however, PLK1 inhibitor will induce reduced immune cell death(ICD).