2. Academic Validation
  3. Inhibition of METTL14 overcomes CDK4/6 inhibitor resistance driven by METTL14-m6A-E2F1-axis in ERα-positive breast cancer

Inhibition of METTL14 overcomes CDK4/6 inhibitor resistance driven by METTL14-m6A-E2F1-axis in ERα-positive breast cancer

  • J Nanobiotechnology. 2025 Jan 3;23(1):3. doi: 10.1186/s12951-024-03021-2.
Chenlin Liu # 1 2,  Dong Fan # 3,  Jiahui Sun # 1,  Guodong Li # 1,  Ruoxin Du 1,  Xiaoshuang Zuo 1,  Kuo Zhang 1,  Wangqian Zhang 1,  Shuning Wang 1,  Xiaojv Li 1 4,  Mingrui Du 1,  Donghui Wang 1,  Qiang Hao 1,  Yingqi Zhang 1,  Meng Li 5,  Cun Zhang 6,  Yuan Gao 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 169 Changle West Road, 710032, Xi'an, People's Republic of China.
  • 2 Department of Occupational and Environmental Health, The Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment, School of Public Health, The Fourth Military Medical University, 710032, Xi'an, People's Republic of China.
  • 3 Department of General Surgery, Tangdu Hospital, The Fourth Military Medical University, 710032, Xi'an, People's Republic of China.
  • 4 Bioinformatics Center of AMMS, Beijing, 100850, People's Republic of China.
  • 5 State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 169 Changle West Road, 710032, Xi'an, People's Republic of China. limeng@fmmu.edu.cn.
  • 6 State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 169 Changle West Road, 710032, Xi'an, People's Republic of China. zhangcun@fmmu.edu.cn.
  • 7 State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Biotechnology Center, School of Pharmacy, The Fourth Military Medical University, 169 Changle West Road, 710032, Xi'an, People's Republic of China. gaoyuan321@fmmu.edu.cn.
  • # Contributed equally.
PMID: 39754249 DOI: 10.1186/s12951-024-03021-2
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.

Keywords

Breast cancer; METTL14; RNA modification; m6A.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-16297A
    99.97%, CDK4/6 Inhibitor
    CDK