2. Academic Validation
  3. RAC1-Amplified and RAC1-A159V Hotspot-Mutated Head and Neck Cancer Sensitive to the Rac Inhibitor EHop-016 In Vivo: A Proof-of-Concept Study

RAC1-Amplified and RAC1-A159V Hotspot-Mutated Head and Neck Cancer Sensitive to the Rac Inhibitor EHop-016 In Vivo: A Proof-of-Concept Study

  • Cancers (Basel). 2025 Jan 23;17(3):361. doi: 10.3390/cancers17030361.
Helen Hoi Yin Chan 1,  Hoi-Lam Ngan 1,  Yuen-Keng Ng 2 3,  Chun-Ho Law 1,  Peony Hiu Yan Poon 1,  Ray Wai Wa Chan 4,  Kwok-Fai Lau 4,  Wenying Piao 1,  Hui Li 1,  Lan Wang 1,  Jason Ying Kuen Chan 5,  Yu-Xiong Su 6,  Thomas Chun Kit Yeung 1,  Eileen Wong 1,  Angela Wing Tung Li 7,  Krista Roberta Verhoeft 7 8,  Yuchen Liu 1,  Yukai He 2 3 9,  Stephen Kwok-Wing Tsui 1,  Gordon B Mills 10,  Vivian Wai Yan Lui 1 2 3
Affiliations

Affiliations

  • 1 School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • 2 Georgia Cancer Center, Augusta University, Augusta, GA 30912, USA.
  • 3 Department of Medicine, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA.
  • 4 School of Life Sciences, Faculty of Science, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • 5 Department of Otorhinolaryngology, Head & Neck Surgery, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • 6 Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, The University of Hong Kong, Hong Kong SAR, China.
  • 7 Department of Pharmacy and Pharmacology, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China.
  • 8 Department of Biomedical Sciences, Li Ka Shing Faculty of Medicine, University of Hong Kong, Hong Kong SAR, China.
  • 9 Department of Biochemistry and Molecular Biology, Medical College of Georgia at Augusta University, Augusta, GA 30912, USA.
  • 10 Division of Oncological Sciences, Knight Cancer Institute, Oregon Health and Sciences University, Portland, OR 97201, USA.
PMID: 39941730 DOI: 10.3390/cancers17030361
Abstract

Objective:RAC1 aberrations in head and neck squamous cell carcinoma (HNSCC) remain clinically inactionable today. Methods: Here, we investigated the clinical significance and potential druggability of RAC1 genomic aberrations in HNSCC. Results: Notably, HPV(-)HNSCC patients bearing the unique HNSCC-prevalent RAC1-A159V hotspot mutation, P29S hotspot and G-box domain mutations, and RAC1 copy number increases all displayed dismal overall survival (TCGA-HNSCC). Here, we demonstrated that all five HNSCC patient-relevant RAC1 aberrations tested (A159V and P29S hotspot mutations, K116N, G15S, and N39S) could significantly drive HNSCC tumoroid growth and/invasion, with A159V, P29S, and K116N mutants being the most potent drivers. Interestingly, transcriptomics analyses revealed that RAC1 mutations and copy increase could both drive PI3K pathway activation, with the A159V mutant associated with the prominent intra-tumoral upregulation of phospho-RPS6(Ser235/236) in patient tumors. Importantly, proof-of-principle Rac targeting with EHop-016 resulted in remarkable antitumor activity in vivo against RAC1-A159V-mutated and RAC1-amplified HNSCC patient-derived xenografts (PDXs) and/engineered models. Lastly, melanoma and endometrial xenograft models bearing endogenous RAC1-amplification and RAC1-A159V mutation were also sensitive to EHop-016 targeting. Conclusions: In principle, RAC1 genomic aberrations in HNSCC can be potentially harnessed for precision drugging.

Keywords

RAC1 amplification; RAC1-A159V hotspot mutation; head and neck squamous cell carcinoma (HNSCC).

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-12810
    99.85%, Rac1/Rac3 抑制剂
    Ras
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