PDF(Pubmed)
Abstract：
Head and neck squamous cell carcinoma (HNSCC) is a highly prevalent malignancy worldwide, with a significant proportion of patients developing recurrent and/or metastatic (R/M) disease. Despite recent advances in therapy, the prognosis for patients with advanced HNSCC remains poor. Here, we present the case of a patient with recurrent metastatic HNSCC harboring an HRAS G12S mutation who achieved a durable response to treatment with tipifarnib, a selective inhibitor of farnesyltransferase. The patient was a 48-year-old woman who had previously received multiple lines of therapy with no significant clinical response. However, treatment with tipifarnib resulted in a durable partial response that lasted 8 months. Serial genomic and transcriptomic analyses demonstrated upregulation of YAP1 and AXL in metastatic lesions compared with the primary tumor, the evolution of the tumor microenvironment from an immune-enriched to a fibrotic subtype with increased angiogenesis, and activation of the PI3K/AKT/mTOR pathway in tipifarnib treatment. Lastly, in HRAS-mutated PDXs and in the syngeneic HRAS model, we demonstrated that tipifarnib efficacy is limited by activation of the AKT pathway, and dual treatment with tipifarnib and the PI3K inhibitor, BYL719, resulted in enhanced anti-tumor efficacy. Our case study highlights the potential of targeting HRAS mutations with tipifarnib in R/M HNSCC and identifies potential mechanisms of acquired resistance to tipifarnib, along with immuno-, chemo-, and radiation therapy. Preclinical results provide a firm foundation for further investigation of drug combinations of HRAS-and PI3K -targeting therapeutics in R/M HRAS-driven HNSCC.
摘要：
头颈部鳞状细胞癌（HNSCC）是全球范围内高度流行的恶性肿瘤，相当比例的患者发展为复发性和/或转移性（R/M）疾病。尽管最近在治疗方面取得了进展，晚期HNSCC患者的预后仍然较差.这里,我们介绍了一例复发的转移性HNSCC患者，该患者具有HRASG12S突变，对替比法尼治疗有持久的反应，法尼基转移酶的选择性抑制剂。该患者是一名48岁的女性，以前接受过多种治疗，没有明显的临床反应。然而,替比法尼治疗导致持续8个月的持久部分反应。连续基因组和转录组学分析显示，与原发肿瘤相比，转移性病变中YAP1和AXL上调，肿瘤微环境从免疫富集到血管生成增加的纤维化亚型的演变，和PI3K/AKT/mTOR通路在替比法尼治疗中的激活。最后,在HRAS突变的PDX和同基因HRAS模型中，我们证明了替比法尼的疗效受到AKT通路激活的限制，替比法尼和PI3K抑制剂双重治疗，BYL719导致增强的抗肿瘤功效。我们的案例研究强调了在R/MHNSCC中用替比法尼靶向HRAS突变的潜力，并确定了对替比法尼的获得性抗性的潜在机制。随着免疫-，化学-，和放射治疗。临床前结果为进一步研究R/MHRAS驱动的HNSCC中HRAS和PI3K靶向疗法的药物组合提供了坚实的基础。
