Cutaneous squamous cell carcinoma (cSCC) is a very common skin malignancy with poor prognosis for patients with locally advanced or metastatic cSCC (mcSCC). PI3K/AKT/mTOR and cell cycle signalling pathways are often dysregulated in mcSCC. A combination drug approach has been theorised to overcome the underwhelming clinical performance of targeted inhibitors as single agents. This study investigates the potential of targeted inhibition of the p110α−subunit of PI3K with PIK-75 or BGT226 (P13Ki), and of CDK1/2/5/9 with dinaciclib (CDKi) as single agents and in combination. The patient−derived mcSCC cell lines, UW-CSCC1 and UW-CSCC2, were used to assess cell viability, migration, cell signalling, cell cycle distribution, and apoptosis. PIK-75, BGT226, and dinaciclib exhibited strong cytotoxic potency as single agents. Notably, the non-malignant HaCaT cell line was unaffected. In 2D cultures, PIK-75 synergistically enhanced the cytotoxic effects of dinaciclib in UW-CSCC2, but not UW-CSCC1. Interestingly, this pattern was reversed in 3D spheroid models. Despite the combination of PIK-75 and dinaciclib resulting in an increase in cell cycle arrest and apoptosis, and reduced cell motility, these differences were largely negligible compared to their single-agent counterpart. The differential responses between the cell lines correlated with driver gene mutation profiles. These findings suggest that personalised medicine approaches targeting PI3K and CDK pathways in combination may yield some benefit for mcSCC, and that more complex 3D models should be considered for drug responsiveness studies in this disease.
皮肤鳞状细胞癌（cSCC）是一种极为常见的皮肤恶性肿瘤，对于局部晚期或转移性cSCC（mcSCC）患者预后较差。PI3K/AKT/mTOR通路及细胞周期信号通路在mcSCC中常出现失调。联合用药策略理论上可改善靶向抑制剂单药疗效不佳的临床现状。本研究探讨了使用PIK-75或BGT226靶向抑制PI3K的p110α亚基（P13Ki），以及使用dinaciclib靶向抑制CDK1/2/5/9（CDKi）作为单药及联合用药的潜力。采用患者来源的mcSCC细胞系UW-CSCC1和UW-CSCC2，评估细胞活力、迁移能力、细胞信号传导、细胞周期分布及凋亡情况。结果显示，PIK-75、BGT226和dinaciclib作为单药均表现出强烈的细胞毒性作用，值得注意的是非恶性HaCaT细胞系未受影响。在二维培养体系中，PIK-75能协同增强dinaciclib对UW-CSCC2的细胞毒性效应，但对UW-CSCC1无此作用。有趣的是，这种模式在三维球状培养模型中呈现相反趋势。尽管PIK-75与dinaciclib联用能增加细胞周期阻滞和凋亡，并降低细胞运动性，但与单药治疗相比，这些差异大多可忽略不计。不同细胞系间的差异反应与驱动基因突变谱相关。这些发现表明，针对PI3K和CDK通路的联合个性化治疗方案可能为mcSCC患者带来一定获益，且在该疾病的药物反应性研究中应考虑采用更复杂的三维模型。
肿瘤(癌症)患者之家