Academic Journal
Inhibition of METTL14 overcomes CDK4/6 inhibitor resistance driven by METTL14-m6A-E2F1-axis in ERα-positive breast cancer
| العنوان: | Inhibition of METTL14 overcomes CDK4/6 inhibitor resistance driven by METTL14-m6A-E2F1-axis in ERα-positive breast cancer |
|---|---|
| المؤلفون: | Chenlin Liu, Dong Fan, Jiahui Sun, Guodong Li, Ruoxin Du, Xiaoshuang Zuo, Kuo Zhang, Wangqian Zhang, Shuning Wang, Xiaojv Li, Mingrui Du, Donghui Wang, Qiang Hao, Yingqi Zhang, Meng Li, Cun Zhang, Yuan Gao |
| المصدر: | Journal of Nanobiotechnology, Vol 23, Iss 1, Pp 1-23 (2025) |
| بيانات النشر: | BMC, 2025. |
| سنة النشر: | 2025 |
| المجموعة: | LCC:Biotechnology LCC:Medical technology |
| مصطلحات موضوعية: | RNA modification, m6A, METTL14, Breast cancer, Biotechnology, TP248.13-248.65, Medical technology, R855-855.5 |
| الوصف: | Abstract CDK4/6i, the first-line drug for treating ERα-positive breast cancer, significantly improves clinical outcomes. However, CDK4/6i resistance often develops and remains a major hurdle, and the underlying mechanisms remain challenging to fully investigate. Here, we used Genome-wide CRISPR/Cas9 library screening combined with single-cell sequencing to screen for molecules mediating CDK4/6i resistance and identified METTL14 as a determinant of CDK4/6i sensitivity. Clinical samples and datasets were analyzed and in vitro and in vivo experiments were performed to confirm the critical function of METTL14 in CDK4/6i resistance. Mechanistically, METTL14 can induce an increase in E2F1 expression in breast cancer cells via an m6A IGF2BP2-dependent mechanism and thus promote CDK4/6i resistance. Furthermore, through a small molecule screen, a novel METTL14 inhibitor named WKYMVM, which can restore sensitivity to CDK4/6i in CDK4/6i-resistant breast cancer cells, was identified. Treatment with folate-conjugated liposomes targeting breast cancer cells that contained both a CDK4/6i and WKYMVM revealed the synergistic effect of METTL14 inhibition with CDK4/6i therapy in a CDK4/6i-resistant PDX model. Together, our findings reveal the mechanism of CDK4/6i resistance and provide a strategy for overcoming CDK4/6i resistance via METTL14 inhibition. Graphical Abstract |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 1477-3155 |
| Relation: | https://doaj.org/toc/1477-3155 |
| DOI: | 10.1186/s12951-024-03021-2 |
| URL الوصول: | https://doaj.org/article/1954187f80a44f9fb3b1be62215d1797 |
| رقم الانضمام: | edsdoj.1954187f80a44f9fb3b1be62215d1797 |
| قاعدة البيانات: | Directory of Open Access Journals |
Full Text Finder | تدمد: | 14773155 |
|---|---|
| DOI: | 10.1186/s12951-024-03021-2 |