Elevating CDCA3 levels enhances tyrosine kinase inhibitor sensitivity in TKI-resistant EGFR mutant non-small-cell lung cancer
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Date
2021
Authors
Sahin, K.B.
Shah, E.T.
Ferguson, G.P.
Molloy, C.
Duijf, P.H.G.
Adams, M.N.
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Journal article
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Cancers, 2021; 13(18, article no. 4651):4651-4651
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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.
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Data source: Supplementary Materials, https://doi.org/10.3390/cancers13184651
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Copyright 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/)