Ji Lu, Pu Leighton, Wang Jinglong, Cao Hongbin, Melemenidis Stavros, Sinha Subarna, Guan Li, Laseinde Eyiwunmi E, von Eyben Rie, Richter Sara A, Nam Jin-Min, Kong Christina, Casey Kerriann M, Graves Edward E, Frock Richard L, Le Quynh Thu, Rankin Erinn B
Department of Radiation Oncology and.
Department of Computer Science, Stanford University, Stanford, California, USA.
JCI Insight. 2025 Jun 9;10(11). doi: 10.1172/jci.insight.184968.
Despite aggressive chemoradiation treatment, the overall survival rate for patients with HPV- head and neck squamous cell carcinoma (HNSCC) remains poor, highlighting the urgent need for more effective drug-radiotherapy combinations to improve the therapeutic index of radiation therapy (RT). The fat mass and obesity-related gene (FTO) is emerging as a promising cancer therapeutic target; however, its role in the RT response has been underexplored. In our study, we found that both genetic and pharmacologic inhibition of FTO enhanced the efficacy of RT in human and mouse HNSCC tumor xenografts. Mechanistically, inhibition of FTO improved the RT response in HPV- HNSCC cells, which was associated with increased DNA damage, reduced efficiency of homology directed repair, and decreased formation of RAD51 homolog 1 (RAD51) foci. Importantly, pharmacologic inhibition of FTO did not exacerbate radiation-induced oral mucositis, a significant normal-tissue toxicity associated with HNSCC RT. In summary, our results indicate a role for FTO in regulating homologous recombination while identifying FTO as a potential therapeutic target to enhance the therapeutic index of RT in HPV- HNSCC treatment.
尽管进行了积极的放化疗，但人乳头瘤病毒（HPV）阴性的头颈部鳞状细胞癌（HNSCC）患者的总生存率仍然很低，这凸显了迫切需要更有效的药物与放疗联合方案来提高放射治疗（RT）的治疗指数。脂肪量与肥胖相关基因（FTO）正成为一个有前景的癌症治疗靶点；然而，其在放疗反应中的作用尚未得到充分研究。在我们的研究中，我们发现对FTO进行基因和药物抑制均可增强放疗对人源和小鼠HNSCC肿瘤异种移植模型的疗效。从机制上讲，抑制FTO可改善HPV阴性HNSCC细胞的放疗反应，这与DNA损伤增加、同源定向修复效率降低以及RAD51同源物1（RAD51）灶形成减少有关。重要的是，对FTO进行药物抑制并不会加重放疗引起的口腔黏膜炎，这是一种与HNSCC放疗相关的严重正常组织毒性。总之，我们的结果表明FTO在调节同源重组中发挥作用，同时确定FTO是提高HPV阴性HNSCC治疗中放疗治疗指数的潜在治疗靶点。
