{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,24]],"date-time":"2026-01-24T09:46:51Z","timestamp":1769248011234,"version":"3.49.0"},"reference-count":51,"publisher":"MDPI AG","issue":"18","license":[{"start":{"date-parts":[[2021,9,16]],"date-time":"2021-09-16T00:00:00Z","timestamp":1631750400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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 CDCA3high 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 CDCA3low tumours or upon the emergence of therapy resistance, might improve the response to EGFR TKIs and benefit patients.<\/jats:p>","DOI":"10.3390\/cancers13184651","type":"journal-article","created":{"date-parts":[[2021,9,16]],"date-time":"2021-09-16T21:38:12Z","timestamp":1631828292000},"page":"4651","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Elevating CDCA3 Levels Enhances Tyrosine Kinase Inhibitor Sensitivity in TKI-Resistant EGFR Mutant Non-Small-Cell Lung Cancer"],"prefix":"10.3390","volume":"13","author":[{"given":"Katherine B.","family":"Sahin","sequence":"first","affiliation":[{"name":"Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7626-1085","authenticated-orcid":false,"given":"Esha T.","family":"Shah","sequence":"additional","affiliation":[{"name":"Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Genevieve P.","family":"Ferguson","sequence":"additional","affiliation":[{"name":"Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Christopher","family":"Molloy","sequence":"additional","affiliation":[{"name":"Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8877-7655","authenticated-orcid":false,"given":"Priyakshi","family":"Kalita-de Croft","sequence":"additional","affiliation":[{"name":"UQ Centre for Clinical Research, Faculty of Medicine, University of Queensland, Herston, QLD 4006, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah A.","family":"Hayes","sequence":"additional","affiliation":[{"name":"Bill Walsh Translational Research Laboratory, Faculty of Medicine and Health, Kolling Institute, University of Sydney, Royal North Shore Hospital, Reserve Road, St Leonards, NSW 2065, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Amanda","family":"Hudson","sequence":"additional","affiliation":[{"name":"Bill Walsh Translational Research Laboratory, Faculty of Medicine and Health, Kolling Institute, University of Sydney, Royal North Shore Hospital, Reserve Road, St Leonards, NSW 2065, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emily","family":"Colvin","sequence":"additional","affiliation":[{"name":"Bill Walsh Translational Research Laboratory, Faculty of Medicine and Health, Kolling Institute, University of Sydney, Royal North Shore Hospital, Reserve Road, St Leonards, NSW 2065, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2011-0584","authenticated-orcid":false,"given":"Hannah","family":"Kamitakahara","sequence":"additional","affiliation":[{"name":"Bill Walsh Translational Research Laboratory, Faculty of Medicine and Health, Kolling Institute, University of Sydney, Royal North Shore Hospital, Reserve Road, St Leonards, NSW 2065, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rozelle","family":"Harvie","sequence":"additional","affiliation":[{"name":"Bill Walsh Translational Research Laboratory, Faculty of Medicine and Health, Kolling Institute, University of Sydney, Royal North Shore Hospital, Reserve Road, St Leonards, NSW 2065, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Csilla","family":"Hasovits","sequence":"additional","affiliation":[{"name":"Bill Walsh Translational Research Laboratory, Faculty of Medicine and Health, Kolling Institute, University of Sydney, Royal North Shore Hospital, Reserve Road, St Leonards, NSW 2065, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5203-0672","authenticated-orcid":false,"given":"Tashbib","family":"Khan","sequence":"additional","affiliation":[{"name":"Mater Research Institute, Translational Research Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8646-9843","authenticated-orcid":false,"given":"Pascal H. G.","family":"Duijf","sequence":"additional","affiliation":[{"name":"Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia"},{"name":"Centre for Data Science, Queensland University of Technology, Brisbane, QLD 4059, Australia"},{"name":"Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0136 Oslo, Norway"},{"name":"Department of Medical Genetics, Oslo University Hospital, 0379 Oslo, Norway"},{"name":"University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4102, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2356-3231","authenticated-orcid":false,"given":"Viive M.","family":"Howell","sequence":"additional","affiliation":[{"name":"Bill Walsh Translational Research Laboratory, Faculty of Medicine and Health, Kolling Institute, University of Sydney, Royal North Shore Hospital, Reserve Road, St Leonards, NSW 2065, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7828-263X","authenticated-orcid":false,"given":"Yaowu","family":"He","sequence":"additional","affiliation":[{"name":"Mater Research Institute, Translational Research Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emma","family":"Bolderson","sequence":"additional","affiliation":[{"name":"Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1054-8486","authenticated-orcid":false,"given":"John D.","family":"Hooper","sequence":"additional","affiliation":[{"name":"Mater Research Institute, Translational Research Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4067-2760","authenticated-orcid":false,"given":"Sunil R.","family":"Lakhani","sequence":"additional","affiliation":[{"name":"UQ Centre for Clinical Research, Faculty of Medicine, University of Queensland, Herston, QLD 4006, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Derek J.","family":"Richard","sequence":"additional","affiliation":[{"name":"Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenneth J.","family":"O\u2019Byrne","sequence":"additional","affiliation":[{"name":"Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia"},{"name":"Cancer Services, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, QLD 4102, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1906-5018","authenticated-orcid":false,"given":"Mark N.","family":"Adams","sequence":"additional","affiliation":[{"name":"Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"394","DOI":"10.3322\/caac.21492","article-title":"Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"68","author":"Bray","year":"2018","journal-title":"CA A Cancer J. 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