Objective:RAC1aberrations in head and neck squamous cell carcinoma (HNSCC) remain clinically inactionable today.Methods:Here, we investigated the clinical significance and potential druggability ofRAC1genomic aberrations in HNSCC.Results:Notably, HPV(−)HNSCC patients bearing the unique HNSCC-prevalentRAC1-A159V hotspot mutation, P29S hotspot and G-box domain mutations, andRAC1copy number increases all displayed dismal overall survival (TCGA-HNSCC). Here, we demonstrated that all five HNSCC patient-relevantRAC1aberrations 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 thatRAC1mutations 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 againstRAC1-A159V-mutated andRAC1-amplified HNSCC patient-derived xenografts (PDXs) and/engineered models. Lastly, melanoma and endometrial xenograft models bearing endogenousRAC1-amplification andRAC1-A159V mutation were also sensitive to EHop-016 targeting.Conclusions:In principle,RAC1genomic aberrations in HNSCC can be potentially harnessed for precision drugging.
目的：目前，头颈部鳞状细胞癌（HNSCC）中的RAC1基因异常在临床上仍缺乏有效干预手段。方法：本研究探讨了HNSCC中RAC1基因组异常的临床意义及其潜在药物靶向性。结果：值得注意的是，携带HNSCC特有的RAC1-A159V热点突变、P29S热点突变及G-box结构域突变，以及RAC1拷贝数增加的HPV(−)HNSCC患者均表现出较差的总生存期（TCGA-HNSCC数据）。实验证明，所有五种与HNSCC患者相关的RAC1异常（A159V和P29S热点突变，K116N、G15S和N39S突变）均能显著驱动HNSCC类肿瘤生长和/或侵袭，其中A159V、P29S和K116N突变体的驱动作用最强。转录组学分析显示，RAC1突变和拷贝数增加均可驱动PI3K通路激活，且在患者肿瘤组织中，A159V突变与磷酸化RPS6（Ser235/236）的显著瘤内上调相关。重要的是，通过EHop-016进行原理验证性Rac靶向治疗，在体内对携带RAC1-A159V突变和RAC1扩增的HNSCC患者来源异种移植模型（PDXs）及工程化模型显示出显著的抗肿瘤活性。最后，携带内源性RAC1扩增和RAC1-A159V突变的黑色素瘤和子宫内膜异种移植模型也对EHop-016靶向治疗敏感。结论：原则上，HNSCC中的RAC1基因组异常具有作为精准药物靶点的潜力。
肿瘤(癌症)患者之家