PO.ET09.05 · 实验与分子治疗
评估axitinib在头颈部鳞状细胞癌中反应的分子机制
Evaluating the molecular mechanism of axitinib response in head and neck squamous cell carcinoma
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
头颈部鳞状细胞癌（HNSCC）是第6大常见癌症，每年新增80万例，是一种极具侵袭性的疾病，总生存率较差且数十年来保持不变。对于发展为复发和转移性（R/M）疾病的患者，治疗选择极为有限，尽管免疫检查点抑制剂（ICI）疗法近期取得成功，但总体反应率仍然较低。为弥补这一知识空白并改善生存，我们的团队完成了一项泛VEGF抑制剂axitinib在R/M患者中的2期临床试验。对该研究肿瘤的基因分析显示，携带PIK3CA或PTEN基因组畸变的患者中有75%的无进展生存期更长，而无PI3K通路改变的患者中这一比例为17%。重要的是，PI3K通路畸变在HNSCC中高度普遍，占所有HNSCC的45-55%，提示具有产生重大临床影响的潜力。在我们的基因工程小鼠模型（GEMM）中，axitinib显著延长了携带K14:Pik3ca-H1047R肿瘤小鼠的总生存期，但对K14:对照肿瘤则无此作用。此外，在HNSCC细胞系中使用体外细胞增殖和存活检测显示，axitinib使细胞数量减少50%，通过蛋白质印迹检测显示可增加gammaH2AX（DNA损伤标志物）蛋白水平，且在PIK3CA突变细胞系中更为有效。此外，在检验其机制时，我们观察到axitinib（而非已知的VEGFR抑制剂Lenvatinib）可在HNSCC细胞系中诱导凋亡。更深入的研究表明，这些HNSCC细胞系并不表达任何已知的axitinib靶点，提示axitinib可能具有额外的、未知的作用机制（MoA）。为检验额外的MoA，我们使用RNA测序对axitinib处理的HNSCC细胞系进行分析，以比较axitinib与其他VEGFR和PI3K抑制剂差异性调控的信号转导通路。未来的研究将使我们能够继续探究axitinib的作用机制及其在PI3K畸变HNSCC中的治疗潜力。我们的发现支持axitinib的临床推进，以及将PI3K基因状态用作预测标志物，以指导这一大批治疗选择有限的HNSCC患者亚群的治疗反应。
查看英文原文 English abstract
Head and Neck Squamous Cell Carcinoma (HNSCC), the 6 th most common cancer with 800,000 new cases each year, is an extremely aggressive disease with poor overall survival that has remained unchanged for several decades. For patients that develop recurrent and metastatic (R/M) disease, treatment options are extremely limited, and despite the recent success of immune checkpoint inhibitor (ICI) therapies, overall response rates remain low. To overcome this gap in knowledge and improve survival, our team completed a Phase 2 clinical trial of the pan-VEGF inhibitor, axitinib, in R/M patients. Genetic analysis of tumors from this study revealed that 75% of patients with genomic aberrations in either PIK3CA or PTEN had a longer progression-free survival compared to 17% in those without a PI3K pathway alteration. Importantly, PI3K pathway aberrations are highly prevalent in HNSCC, accounting for 45-55% of all HNSCCs, suggesting the potential for a substantial clinical impact. In our genetically engineered mouse model (GEMM), axitinib significantly extended the overall survival of mice with K14:Pik3ca-H1047R, but not K14:control, tumors. Additionally, the use of in vitro cell proliferation and survival assays in HNSCC cell lines has shown that axitinib reduces cell numbers by 50%, increases gammaH2AX (DNA damage marker) protein levels as measured by western blots, and is more effective in PIK3CA mutant cell lines. Further, when testing the mechanism, we observed that axitinib, but not Lenvatinib (known VEGFR inhibitor), induced apoptosis in HNSCC cell lines. Deeper investigation showed that the HNSCC cell lines did not express any known axitinib targets, suggesting that axitinib may have an additional, unknown mechanism of action (MoA). To test for additional MoA, we used RNA sequencing of axitinib-treated HNSCC cell lines to compare the signal transduction pathways differentially regulated by axitinib compared to other VEGFR and PI3K inhibitors. Future studies will allow us to continue investigating axitinib's mechanism of action and its therapeutic potential in PI3K aberrant HNSCC. Our findings support clinical advancement of axitinib and use of PI3K genetic status as a predictive marker for therapeutic response for a large subset of HNSCC patients with limited therapeutic options.
利益披露 Disclosure
B. Karaj,
University of Michigan Patent, University of Michigan holds a patent for axitinib use in PI3K mutant cancers.
J. Wang, None.
P. L. Swiecicki,
University of Michigan Patent, University of Michigan holds a patent for use of axitinib in PI3K cancers.
A. Teng, None.
J. Brenner,
University of Michigan Patent, University of Michigan holds a patent for use of axitinib in PI3K cancers.