Elevating CDCA3 Levels Enhances Tyrosine Kinase Inhibitor Sensitivity in TKI-Resistant EGFR Mutant Non-Small-Cell Lung Cancer
| العنوان: | Elevating CDCA3 Levels Enhances Tyrosine Kinase Inhibitor Sensitivity in TKI-Resistant EGFR Mutant Non-Small-Cell Lung Cancer |
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| المؤلفون: | Yaowu He, Csilla Hasovits, Amanda L. Hudson, Rozelle Harvie, Viive M. Howell, Katherine B. Sahin, Priyakshi Kalita-de Croft, Christopher Molloy, Sunil R. Lakhani, Sarah A. Hayes, Hannah Kamitakahara, Tashbib Khan, Genevieve P. Ferguson, Derek J. Richard, Kenneth J. O'Byrne, Esha T. Shah, Emma Bolderson, Mark N. Adams, Emily Colvin, Pascal H.G. Duijf, John D. Hooper |
| المساهمون: | Sahin, Katherine B, Shah, Esha T, Ferguson, Genevieve P, Molloy, Christopher, Duijf, Pascal HG, Adams, Mark N |
| المصدر: | Cancers Cancers, Vol 13, Iss 4651, p 4651 (2021) Volume 13 Issue 18 |
| بيانات النشر: | MDPI AG, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Cancer Research, medicine.drug_class, tyrosine kinase inhibitor (TKI), non-small-cell lung cancer (NSCLC), non-small cell lung cancer (NSCLC), Article, Receptor tyrosine kinase, Tyrosine-kinase inhibitor, T790M, medicine, Epidermal growth factor receptor, Lung cancer, RC254-282, biology, business.industry, acquired resistance, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, medicine.disease, epidermal growth factor receptor (EGFR), respiratory tract diseases, cell division cycle-associated protein 3 (CDCA3), Oncology, biology.protein, Cancer research, biomarker, Casein kinase 2, business, Tyrosine kinase |
| الوصف: | Simple Summary Resistance to tyrosine kinase inhibitors (TKIs) that target common non-small-cell lung cancer mutations within the epidermal growth factor receptor (EGFR) is a primary clinical issue. The aim of our study was to determine whether the protein cell division cycle-associated protein 3 (CDCA3) might be a biomarker for TKI response in EGFR mutant lung cancer. Our previous work has demonstrated that CDCA3 is a marker of chemotherapy sensitivity in lung cancer. We provide evidence that CDCA3 levels are increased in EGFR mutant lung cancer and these levels are associated with sensitivity to TKIs. In addition, increasing the levels of CDCA3 enhances TKI sensitivity in models of TKI-resistant EGFR mutant lung cancer. Our findings propose that strategies to upregulate CDCA3 levels might improve TKI response in EGFR mutant lung cancer. 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 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. |
| وصف الملف: | application/pdf |
| تدمد: | 2072-6694 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a2d143bd6bdc2dce4e41407c1d4df887 https://doi.org/10.3390/cancers13184651 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....a2d143bd6bdc2dce4e41407c1d4df887 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 20726694 |
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