Year-end Sale % OFF 
Abstract
Platinum-based chemotherapy remains the cornerstone of treatment for most non-small cell lung cancer (NSCLC) cases either as maintenance therapy or in combination with immunotherapy. However, resistance remains a primary issue. Our findings point to the possibility of exploiting levels of cell division cycle associated protein-3 (CDCA3) to improve response of NSCLC tumours to therapy. We demonstrate that in patients and in vitro analyses, CDCA3 levels correlate with measures of genome instability and platinum sensitivity, whereby CDCA3high tumours are sensitive to cisplatin and carboplatin. In NSCLC, CDCA3 protein levels are regulated by the ubiquitin ligase APC/C and cofactor Cdh1. Here, we identified that the degradation of CDCA3 is modulated by activity of casein kinase 2 (CK2) which promotes an interaction between CDCA3 and Cdh1. Supporting this, pharmacological inhibition of CK2 with CX-4945 disrupts CDCA3 degradation, elevating CDCA3 levels and increasing sensitivity to platinum agents. We propose that combining CK2 inhibitors with platinum-based chemotherapy could enhance platinum efficacy in CDCA3low NSCLC tumours and benefit patients.
Highlights
Platinum-based chemotherapy remains the cornerstone of treatment for most non-small cell lung cancer (NSCLC) cases either as maintenance therapy or in combination with immunotherapy
This is in line with our observation that cisplatininduced DNA damage causes an upregulation of cell division cycle associated protein-3 (CDCA3) protein via evasion of APC/CCdh1-mediated degradation (Figs. 2 and 3), suggesting that upregulation of CDCA3 expression is symptomatic of, and not causal of genome instability
Upregulation of CDCA3 levels by ectopic expression resulted in enhanced sensitivity to cisplatin and carboplatin (Fig. 6a, b)
Summary
Platinum-based chemotherapy remains the cornerstone of treatment for most non-small cell lung cancer (NSCLC) cases either as maintenance therapy or in combination with immunotherapy. Our findings point to the possibility of exploiting levels of cell division cycle associated protein-3 (CDCA3) to improve response of NSCLC tumours to therapy. In the search for novel biomarkers or therapeutic targets, we have studied the protein cell division cycle associated protein-3 (CDCA3), known as trigger of mitosis entry 1 (TOME-1). This protein primarily modulates cell cycle progression from the G2 phase to mitosis. We demonstrate that while CDCA3 protein levels are regulated by the anaphase-promoting complex/cyclosome (APC/C) in NSCLC, pharmacological strategies to block this protein–protein interaction enhance sensitivity to platinum agents
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
