G1/S 转换的完整调节使食管鳞状细胞癌对 PI3Kα 抑制剂敏感,Signal Transduction and Targeted Therapy

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G1/S 转换的完整调节使食管鳞状细胞癌对 PI3Kα 抑制剂敏感
Signal Transduction and Targeted Therapy ( IF 40.8 ) Pub Date : 2023-04-12 , DOI: 10.1038/s41392-023-01359-x
Xu Zhang _{1,

2} , Yuxiang Wang ₁ , Xi Zhang ₁ , Yanyan Shen ₁ , Kang Yang ₃ , Qingyang Ma ₄ , Yuemei Qiao ₅ , Jiajie Shi ₁ , Yi Wang ₁ , Lan Xu ₁ , Biyu Yang ₁ , Gaoxiang Ge ₅ , Landian Hu ₄ , Xiangyin Kong ₄ , Chunhao Yang ₆ , Yi Chen _{1,

2} , Jian Ding _{1,

2} , Linghua Meng _{1,

2,

3}

Affiliation

磷脂酰肌醇 3-激酶 α (PI3Kα) 抑制剂目前正在评估食管鳞状细胞癌 (ESCC) 的治疗效果。确定潜在的生物标志物以预测或监测 PI3Kα 抑制剂的疗效以提高 ESCC 的临床反应率非常重要。在这里，带有CCND1的 ESCC PDX发现扩增对 CYH33 更敏感，CYH33 是一种新型 PI3Kα 选择性抑制剂，目前正在临床试验中用于治疗包括 ESCC 在内的晚期实体瘤。与耐药细胞相比，在 CYH33 敏感的 ESCC 细胞中发现细胞周期蛋白 D1、p21 和 Rb 水平升高。CYH33 在 G1 期显着抑制敏感细胞而非耐药细胞，这与 p21 的积累和 CDK4/6 和 CDK2 对 Rb 磷酸化的抑制有关。Rb 的低磷酸化减弱了 E2F1 对 SKP2 的转录激活，这反过来又阻碍了 SKP2 介导的 p21 降解并增强了 p21 的积累。此外，CDK4/6 抑制剂使耐药 ESCC 细胞和 PDX 对 CYH33 敏感。这些发现为评估 PI3Kα 抑制剂在携带扩增的 ESCC 患者中的作用机制提供了依据。CCND1和与 CDK4/6 抑制剂联合治疗 ESCC 与精通 Rb。

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Intact regulation of G1/S transition renders esophageal squamous cell carcinoma sensitive to PI3Kα inhibitors

Phosphatidylinositol 3-kinase alpha (PI3Kα) inhibitors are currently evaluated for the therapy of esophageal squamous cell carcinoma (ESCC). It is of great importance to identify potential biomarkers to predict or monitor the efficacy of PI3Kα inhibitors in an aim to improve the clinical responsive rate in ESCC. Here, ESCC PDXs with CCND1 amplification were found to be more sensitive to CYH33, a novel PI3Kα-selective inhibitor currently in clinical trials for the treatment of advanced solid tumors including ESCC. Elevated level of cyclin D1, p21 and Rb was found in CYH33-sensitive ESCC cells compared to those in resistant cells. CYH33 significantly arrested sensitive cells but not resistant cells at G1 phase, which was associated with accumulation of p21 and suppression of Rb phosphorylation by CDK4/6 and CDK2. Hypo-phosphorylation of Rb attenuated the transcriptional activation of SKP2 by E2F1, which in turn hindered SKP2-mediated degradation of p21 and reinforced accumulation of p21. Moreover, CDK4/6 inhibitors sensitized resistant ESCC cells and PDXs to CYH33. These findings provided mechanistic rationale to evaluate PI3Kα inhibitors in ESCC patients harboring amplified CCND1 and the combined regimen with CDK4/6 inhibitors in ESCC with proficient Rb.

更新日期：2023-04-12

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