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  3. Plasma membrane-associated ARAF condensates fuel RAS-related cancer drug resistance

Plasma membrane-associated ARAF condensates fuel RAS-related cancer drug resistance

  • Nat Chem Biol. 2025 Jan 27. doi: 10.1038/s41589-024-01826-8.
Wen Li # 1,  Xiaoxian Shi # 1,  Caiwei Tan # 2,  Zhaodi Jiang 3,  Mingyi Li 1,  Zhiheng Ji 4,  Jing Zhou 1,  Mengxin Luo 2,  Zuyan Fan 1,  Zhifan Ding 5,  Yue Fang 1,  Jun Sun 6,  Junjun Ding 7,  Huasong Lu 1,  Weirui Ma 1,  Wei Xie 8 9,  Wenjing Su 10 11
Affiliations

Affiliations

  • 1 Zhejiang Key Laboratory of Molecular Cancer Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China.
  • 2 Zhejiang University College of Pharmaceutical Sciences, Hangzhou, China.
  • 3 The National Institute of Biological Sciences and Tsinghua Institute of Multidisciplinary Biomedical Research, Tsinghua University, Beijing, China.
  • 4 The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 5 Department of Urology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • 6 Department of Thoracic Surgery and West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, China.
  • 7 Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
  • 8 Zhejiang University College of Pharmaceutical Sciences, Hangzhou, China. xie_wei@zju.edu.cn.
  • 9 The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. xie_wei@zju.edu.cn.
  • 10 Zhejiang Key Laboratory of Molecular Cancer Biology, Life Sciences Institute, Zhejiang University, Hangzhou, China. wenjingsu@zju.edu.cn.
  • 11 The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China. wenjingsu@zju.edu.cn.
  • # Contributed equally.
PMID: 39870764 DOI: 10.1038/s41589-024-01826-8
Abstract

Raf protein kinases are major Ras effectors that function by phosphorylating MEK. Although all three Raf isoforms share a conserved Ras binding domain and bind to GTP-loaded Ras, only ARAF uniquely enhances Ras activity. Here we uncovered the molecular basis of ARAF in regulating Ras activation. The disordered N-terminal sequence of ARAF drives self-assembly, forming ARAF-RAS condensates tethered to the plasma membrane. These structures concentrate active Ras locally, impeding NF1-mediated negative regulation of Ras, thereby fostering receptor tyrosine kinase (RTK)-triggered Ras activation. In RAS-mutant tumors, loss of the ARAF N terminus sensitizes tumor cells to pan-RAF inhibition. In hormone-sensitive cancers, increased ARAF condensates drive endocrine therapy resistance, whereas ARAF depletion reverses RTK-dependent resistance. Our findings delineate ARAF-RAS protein condensates as distinct subcellular structures sustaining Ras activity and facilitating oncogenic Ras signaling. Targeting ARAF-RAS condensation may offer a strategy to overcome drug resistance in both wild-type and mutant ARAF-mediated scenarios.

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