Aurora Kinase B inhibition in non-small cell lung and head and neck cancer

Non-small cell lung cancer (NCSLC) and Head and Neck Squamous Cell cancer (HNSCC) are two of the most common tumour sites treated in oncology practices in the United Kingdom (UK). The survival for NSCLC and HNSCC is poor, with 10% and 19-59 % over ten years (Cancer Research UK,” 2023). Poor survival has been linked with early local recurrence and invariable metastatic disease. Aurora Kinase A (AURKA) and Aurora Kinase B (AURKB) are both overexpressed in these cancers and are linked with poor survival rates.

We have hypothesised that increased AURKA and AURKB expression is linked with radioresistance in NSCLC and HNSCC; inhibitors of both proteins can sensitise cell lines in these cancer groups to irradiation (IR).
We demonstrate that AURKA inhibition radiosensitises NSCLC cells in vitro in a p53 dependent manner. We demonstrate that AURKB inhibition using Barasertib reduces cell survival in vitro in both NSCLC and HNSCC, which is not dependent on p53 expression. We demonstrate that Barasertib leads to radiosensitisation of NSCLC cells in vitro in a non-p53 dependent manner, but we could not demonstrate radiosensitisation in any HNSCC cell line.

We showed that combining different chemotherapy drugs with Barasertib led to radiosensitisation of H460 cells; this was possibly dependent on the mechanism of action of the chemotherapy agent.
We showed that adding Barasertib leads to increased levels of slippage in NSCLC (A549, H520) and HNSCC cell lines (UPCI-SCC72, SCC89). We found no direct effects on the cell cycle when NSCLC and HNSCC cell lines were exposed to Barasertib. We then showed that AURKB inhibition increased polyploidy when UPCI-SCC72 and SCC89 cells were exposed to Barasertib over 24 hours.

We demonstrated that AURKB and AURKA show promise as prognostic biomarkers in NSCLC, whereas AURKA alone is a promising biomarker in the HNSCC oropharyngeal subtype. The results of our Prospective Study (looking at NSCLC patients who underwent radical radiotherapy at the Weston Park Cancer Centre) did not show a correlation between AURKA expression and patient Overall survival (OS) and progression-free survival (PFS). AURKB immunohistochemistry (IHC) optimisation was done after to assess for correlation between expression and survival. Differential staining can be demonstrated in H460 cell pellets but requires more optimisation to demonstrate staining in lung tissue confidently.

Finally, we wrote a phase one trial protocol looking at the combination of Barasertib and IR, which we hope to use in the future if the results of the preclinical work are promising.