Cell-cycle pathway impairments resulting in CDK4 and 6 activation are frequently observed in human papillomavirus (HPV)-negative squamous cell carcinoma of the head and neck (SCCHN). We investigated the activity of ribociclib, a CDK4/6 inhibitor, in SCCHN models with the aim of identifying predictive biomarkers of response. HPV-negative or HPV-positive SCCHN cell lines (n = 8) and patient-derived tumor xenograft (PDTX) models (n = 6) were used. The models were classified according to their sensitivity to ribociclib to investigate potential predictive biomarkers. Ribociclib had a cytostatic effect in some HPV-negative SCCHN models but had no effect in HPV-positive models. In SCCHN cell lines and PDTXs, the retinoblastoma (Rb) protein expression level correlated with ribociclib activity. Rb knockdown was, however, not sufficient to block G0–G1 arrest induced by ribociclib in Detroit-562 where p107, p130, and Forkhead BOX M1 (FOXM1) were also implicated in ribociclib activity. Cell lines harboring epithelial-to-mesenchymal transition (EMT) features were less sensitive to ribociclib than those with an epithelial phenotype. Rb downregulation induced EMT in our Rb-expressing SCCHN cell lines. However, ribociclib still had significant activity in one PDTX model with high Rb and vimentin expression, suggesting that the presence of vimentin alone is not enough to induce ribociclib resistance. These findings suggest that CDK4/6 inhibitors should be investigated in patients with HPV-negative SCCHN with high Rb expression and an epithelial phenotype. Although these biomarkers are not predictive in all cases, they may enrich the population that could benefit from CDK4/6 inhibitors.

中文翻译：

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瑞博西尼在头颈部鳞状细胞癌中的临床前活性

在人乳头瘤病毒 (HPV) 阴性的头颈部鳞状细胞癌 (SCCHN) 中经常观察到导致 CDK4 和 6 激活的细胞周期通路损伤。我们研究了 CDK4/6 抑制剂 ribociclib 在 SCCHN 模型中的活性，目的是确定反应的预测生物标志物。使用了 HPV 阴性或 HPV 阳性 SCCHN 细胞系（n = 8）和患者来源的肿瘤异种移植（PDTX）模型（n = 6）。这些模型根据它们对 ribociclib 的敏感性进行分类，以研究潜在的预测生物标志物。Ribociclib 在一些 HPV 阴性 SCCHN 模型中具有细胞抑制作用，但在 HPV 阳性模型中没有作用。在 SCCHN 细胞系和 PDTX 中，视网膜母细胞瘤 (Rb) 蛋白表达水平与 ribociclib 活性相关。然而，Rb 击倒是 不足以阻止 ribociclib 在底特律 562 中诱导的 G0-G1 停滞，其中 p107、p130 和 Forkhead BOX M1 (FOXM1) 也与 ribociclib 活性有关。具有上皮间质转化 (EMT) 特征的细胞系对 ribociclib 的敏感性低于具有上皮表型的细胞系。Rb 下调在我们表达 Rb 的 SCCHN 细胞系中诱导 EMT。然而，ribociclib 在一个具有高 Rb 和波形蛋白表达的 PDTX 模型中仍然具有显着活性，这表明单独存在波形蛋白不足以诱导 ribociclib 抗性。这些发现表明，应在 Rb 高表达和上皮表型的 HPV 阴性 SCCHN 患者中研究 CDK4/6 抑制剂。虽然这些生物标志物并非在所有情况下都能预测，