Elevating CDCA3 Levels Enhances Tyrosine Kinase Inhibitor Sensitivity in TKI-Resistant EGFR Mutant Non-Small-Cell Lung Cancer

SIMPLE SUMMARY: Resistance to tyrosine kinase inhibitors (TKIs) that target common non-small-cell lung cancer mutations within the epidermal growth factor receptor (EGFR) is a primary clinical issue. The aim of our study was to determine whether the protein cell division cycle-associated protein 3 (CDCA3) might be a biomarker for TKI response in EGFR mutant lung cancer. Our previous work has demonstrated that CDCA3 is a marker of chemotherapy sensitivity in lung cancer. We provide evidence that CDCA3 levels are increased in EGFR mutant lung cancer and these levels are associated with sensitivity to TKIs. In addition, increasing the levels of CDCA3 enhances TKI sensitivity in models of TKI-resistant EGFR mutant lung cancer. Our findings propose that strategies to upregulate CDCA3 levels might improve TKI response in EGFR mutant lung cancer. ABSTRACT: Tyrosine kinase inhibitors (TKIs) are the first-line therapy for non-small-cell lung cancers (NSCLC) that harbour sensitising mutations within the epidermal growth factor receptor (EGFR). However, resistance remains a key issue, with tumour relapse likely to occur. We have previously identified that cell division cycle-associated protein 3 (CDCA3) is elevated in adenocarcinoma (LUAD) and correlates with sensitivity to platinum-based chemotherapy. Herein, we explored whether CDCA3 levels were associated with EGFR mutant LUAD and TKI response. We demonstrate that in a small-cohort tissue microarray and in vitro LUAD cell line panel, CDCA3 protein levels are elevated in EGFR mutant NSCLC as a result of increased protein stability downstream of receptor tyrosine kinase signalling. Here, CDCA3 protein levels correlated with TKI potency, whereby CDCA3(high) EGFR mutant NSCLC cells were most sensitive. Consistently, ectopic overexpression or inhibition of casein kinase 2 using CX-4945, which pharmacologically prevents CDCA3 degradation, upregulated CDCA3 levels and the response of T790M(+) H1975 cells and two models of acquired resistance to TKIs. Accordingly, it is possible that strategies to upregulate CDCA3 levels, particularly in CDCA3(low) tumours or upon the emergence of therapy resistance, might improve the response to EGFR TKIs and benefit patients.