The dual pathway inhibitor rigosertib is effective in direct-patient tumor xenografts of head and neck squamous cell carcinomas

Rigosertib treatment of head and neck squamous cell cancer The dual pathway inhibitor rigosertib inhibits phosphoinositide 3-kinase (PI3K) pathway activation as well as polo-like kinase 1 (PLK1) activity across a broad spectrum of cancer cell lines. The importance of PIK3CA alterations in head and neck squamous cell cancer (HNSCC) has raised interest in exploring agents targeting PI3K, the product of PIK3CA. The genetic and molecular basis of rigosertib treatment response was investigated in a panel of 16 HNSCC cell lines, and direct patient tumor xenografts from 8 HNSCC patients (4 HPV16-positive). HNSCC cell lines and xenografts were characterized by pathway enrichment gene expression analysis, exon sequencing, gene copy number, western blotting, and IHC. Rigosertib had potent antiproliferative effects on 11 of the 16 HPV- HNSCC cell lines. Treatment sensitivity was confirmed in two cell lines using an orthotopic in vivo xenograft model. Growth reduction after rigosertib treatment was observed in 3/8 HNSCC direct patient tumor lines. The responsive tumor lines carried a combination of a PI3KCA activating event (amplification or mutation) and a p53 inactivating event (either HPV16-mediated or mutation-mediated TP53 inactivation). In this study, we evaluated the in vitro and in vivo efficacy of rigosertib in both HPV+ and HPV- HNSCCs focusing on inhibition of the PI3K pathway. Although consistent inhibition of the PI3K pathway was not evident in HNSCC, we identified a combination of PI3K/TP53 events necessary, but not sufficient for rigosertib-sensitivity. Sixteen HNSCC lines data were profiled at baseline to find differentially expressed genes and pathways sensitive to rigosertib.

本数据集聚焦利戈塞替尼治疗头颈鳞状细胞癌（Head and Neck Squamous Cell Cancer, HNSCC）的相关研究。双通路抑制剂利戈塞替尼（Rigosertib）可在广泛的癌细胞系中同时抑制磷脂酰肌醇3-激酶（phosphoinositide 3-kinase, PI3K）通路激活与polo样激酶1（polo-like kinase 1, PLK1）活性。PIK3CA基因变异在头颈鳞状细胞癌中的重要性，使得靶向PIK3CA编码产物PI3K的治疗药物受到广泛关注。本研究在包含16株头颈鳞状细胞癌细胞系的细胞株库，以及8例头颈鳞状细胞癌患者来源的异种移植瘤（其中4例为人乳头瘤病毒16型（HPV16）阳性）中，探究了利戈塞替尼治疗应答的遗传与分子基础。研究人员通过通路富集基因表达分析、外显子测序、基因拷贝数检测、蛋白质印迹（western blotting）、免疫组化（immunohistochemistry, IHC）对上述头颈鳞状细胞癌细胞系与异种移植瘤进行了特征鉴定。利戈塞替尼对16株HPV阴性头颈鳞状细胞癌细胞系中的11株展现出强效抗增殖活性。研究人员通过原位体内异种移植瘤模型，在两株细胞系中验证了治疗敏感性。在8例患者来源的头颈鳞状细胞癌移植瘤中，3例经利戈塞替尼治疗后出现肿瘤生长抑制。应答性肿瘤株同时携带PI3KCA激活事件（基因扩增或突变）以及p53失活事件，包括HPV16介导的TP53（Tumor Protein p53, TP53）失活，或TP53突变介导的p53失活。本研究评估了利戈塞替尼在HPV阳性与HPV阴性头颈鳞状细胞癌中的体外与体内药效，重点关注其对PI3K通路的抑制作用。尽管在头颈鳞状细胞癌中未观察到PI3K通路的持续抑制，但研究人员确定了PI3K/TP53联合变异是利戈塞替尼敏感性的必要而非充分条件。本数据集对16株头颈鳞状细胞癌细胞系的基线表达谱进行了分析，以筛选对利戈塞替尼敏感的差异表达基因与通路。