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

Katherine B Sahin; Esha T Shah; Genevieve P Ferguson; Christopher Molloy; Priyakshi Kalita-de Croft; Sarah A Hayes; Amanda Hudson; Emily Colvin; Hannah Kamitakahara; Rozelle Harvie; Csilla Hasovits; Tashbib Khan; Pascal H G Duijf; Viive M Howell; Yaowu He; Emma Bolderson; John D Hooper; Sunil R Lakhani; Derek J Richard; Kenneth J O'Byrne; Mark N Adams

doi:10.3390/cancers13184651

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

Cancers (Basel). 2021 Sep 16;13(18):4651. doi: 10.3390/cancers13184651.

Authors

Katherine B Sahin¹, Esha T Shah¹, Genevieve P Ferguson¹, Christopher Molloy¹, Priyakshi Kalita-de Croft², Sarah A Hayes³, Amanda Hudson³, Emily Colvin³, Hannah Kamitakahara³, Rozelle Harvie³, Csilla Hasovits³, Tashbib Khan⁴, Pascal H G Duijf^{1

5

6

7

8}, Viive M Howell³, Yaowu He⁴, Emma Bolderson¹, John D Hooper⁴, Sunil R Lakhani², Derek J Richard¹, Kenneth J O'Byrne^{1

9}, Mark N Adams¹

Affiliations

¹ Centre for Genomics and Personalised Health, School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, QLD 4059, Australia.
² UQ Centre for Clinical Research, Faculty of Medicine, University of Queensland, Herston, QLD 4006, Australia.
³ 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.
⁴ Mater Research Institute, Translational Research Institute, The University of Queensland, Woolloongabba, QLD 4102, Australia.
⁵ Centre for Data Science, Queensland University of Technology, Brisbane, QLD 4059, Australia.
⁶ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, 0136 Oslo, Norway.
⁷ Department of Medical Genetics, Oslo University Hospital, 0379 Oslo, Norway.
⁸ University of Queensland Diamantina Institute, Faculty of Medicine, The University of Queensland, Brisbane, QLD 4102, Australia.
⁹ Cancer Services, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, QLD 4102, Australia.

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.

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