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

Cancers

Viive M. Howell¹  Csilla Hasovits¹  Rozelle Harvie¹  Sarah A. Hayes¹  Amanda Hudson¹  Emily Colvin¹  Hannah Kamitakahara¹  Emma Bolderson²  Christopher Molloy²  Kenneth J. O’Byrne²  Pascal H. G. Duijf²  Esha T. Shah²  Derek J. Richard²  Genevieve P. Ferguson²  Katherine B. Sahin²  Mark N. Adams²  Yaowu He³  Tashbib Khan³  John D. Hooper³  Sunil R. Lakhani⁴  Priyakshi Kalita-de Croft⁴ 

[1] 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;Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia;Mater Research Institute, Translational Research Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia;UQ Centre for Clinical Research, Faculty of Medicine, University of Queensland, Herston, QLD 4006, Australia;

关键词: non-small-cell lung cancer (NSCLC);    epidermal growth factor receptor (EGFR);    tyrosine kinase inhibitor (TKI);    cell division cycle-associated protein 3 (CDCA3);    acquired resistance;    biomarker;   

DOI  :  10.3390/cancers13184651

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown