Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Center for Translational Cancer Research, Institute of Biosciences and Technology, Texas A&M College of Medicine, Houston, Texas.
Clin Cancer Res. 2022 Oct 14;28(20):4479-4493. doi: 10.1158/1078-0432.CCR-22-1627.
Human papillomavirus (HPV) causes >5% of cancers, but no therapies uniquely target HPV-driven cancers.
We tested the cytotoxic effect of 864 drugs in 16 HPV-positive and 17 HPV-negative human squamous cancer cell lines. We confirmed apoptosis in vitro and in vivo using patient-derived xenografts. Mitotic pathway components were manipulated with drugs, knockdown, and overexpression.
Aurora kinase inhibitors were more effective in vitro and in vivo in HPV-positive than in HPV-negative models. We hypothesized that the mechanism of sensitivity involves retinoblastoma (Rb) expression because the viral oncoprotein E7 leads to Rb protein degradation, and basal Rb protein expression correlates with Aurora inhibition-induced apoptosis. Manipulating Rb directly, or by inducing E7 expression, altered cells' sensitivity to Aurora kinase inhibitors. Rb affects expression of the mitotic checkpoint genes MAD2L1 and BUB1B, which we found to be highly expressed in HPV-positive patient tumors. Knockdown of MAD2L1 or BUB1B reduced Aurora kinase inhibition-induced apoptosis, whereas depletion of the MAD2L1 regulator TRIP13 enhanced it. TRIP13 is a potentially druggable AAA-ATPase. Combining Aurora kinase inhibition with TRIP13 depletion led to extensive apoptosis in HPV-positive cancer cells but not in HPV-negative cancer cells.
Our data support a model in which HPV-positive cancer cells maintain a balance of MAD2L1 and TRIP13 to allow mitotic exit and survival in the absence of Rb. Because it does not affect cells with intact Rb function, this novel combination may have a wide therapeutic window, enabling the effective treatment of Rb-deficient cancers.
人乳头瘤病毒（HPV）导致超过 5%的癌症，但没有专门针对 HPV 驱动的癌症的治疗方法。
我们在 16 种 HPV 阳性和 17 种 HPV 阴性的人鳞状癌细胞系中测试了 864 种药物的细胞毒性作用。我们使用患者来源的异种移植物在体外和体内证实了细胞凋亡。使用药物、敲低和过表达来操纵有丝分裂途径成分。
与 HPV 阴性模型相比，Aurora 激酶抑制剂在 HPV 阳性模型中体外和体内的效果更为显著。我们假设这种敏感性的机制涉及视网膜母细胞瘤（Rb）的表达，因为病毒癌蛋白 E7 导致 Rb 蛋白降解，并且基础 Rb 蛋白表达与 Aurora 抑制诱导的凋亡相关。直接操纵 Rb，或通过诱导 E7 表达，改变了细胞对 Aurora 激酶抑制剂的敏感性。Rb 影响有丝分裂检查点基因 MAD2L1 和 BUB1B 的表达，我们发现这些基因在 HPV 阳性患者肿瘤中高度表达。MAD2L1 或 BUB1B 的敲低减少了 Aurora 激酶抑制诱导的细胞凋亡，而 MAD2L1 调节剂 TRIP13 的耗竭则增强了凋亡。TRIP13 是一种潜在的可用药的 AAA-ATPase。Aurora 激酶抑制与 TRIP13 耗竭联合使用导致 HPV 阳性癌细胞发生广泛凋亡，但 HPV 阴性癌细胞不会发生凋亡。
我们的数据支持这样一种模型，即 HPV 阳性癌细胞维持 MAD2L1 和 TRIP13 的平衡，以允许在没有 Rb 的情况下有丝分裂退出和存活。因为它不会影响具有完整 Rb 功能的细胞，这种新的组合可能具有广泛的治疗窗口，能够有效治疗 Rb 缺失的癌症。
