Zhang Xu, Xu Jiao, Wang Xuan, Xu Lan, Zhang Xi, Wang Yi, Jiang Shujuan, Zhang Yixiang, Ding Jian, Qing Chen, Meng Linghua
Division of Anti-tumor Pharmacology, State Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
School of Pharmaceutical Sciences & Yunnan Key Laboratory of Pharmacology for Natural Products, Kunming Medical University, Yunnan, China.
Cell Death Dis. 2025 Jun 18;16(1):457. doi: 10.1038/s41419-025-07767-x.
The hyperactivation of the PI3K pathway in head and neck squamous cell carcinoma (HNSCC) suggests that targeting PI3K is a potential therapeutic strategy. CYH33 is a novel PI3Kα-selective inhibitor discovered by our group, which is currently undergoing a phase I clinical trial (NCT03544905) for the treatment of advanced solid tumors including HNSCC. However, there is an urgent need to elucidate its mechanism of action and improve its efficacy against HNSCC. In this study, we found that CYH33 displayed promising but variable therapeutic activity against HNSCC. Inhibition of PI3K/Akt pathway by CYH33 was not sufficient for its activity against HNSCC. Tandem-Mass-Tag (TMT) phosphoproteomics were performed to reveal comprehensive regulation of kinome by CYH33. Particularly, attenuation of Erk phosphorylation was associated with the sensitivity of HNSCC cells to CYH33. Mechanistically, inhibition of PI3K by CYH33 blocked the PIP3 production and attenuated the membrane localization and phosphorylation of GAB1, resulting in reduced Erk phosphorylation and ultimately inhibition of cell proliferation in sensitive HNSCC cells. Meanwhile, activation of EGFR induced GAB1 phosphorylation independent of PI3K in HNSCC cells. Concurrent inhibition of EGFR synergistically potentiated the activity of CYH33 against HNSCC. These findings revealed the insight mechanism of CYH33 against HNSCC and provided rational combination regimen for HNSCC treatment.
头颈部鳞状细胞癌（HNSCC）中PI3K通路的过度激活表明，靶向PI3K是一种潜在的治疗策略。CYH33是我们团队发现的一种新型PI3Kα选择性抑制剂，目前正在进行一项I期临床试验（NCT03544905），用于治疗包括HNSCC在内的晚期实体瘤。然而，迫切需要阐明其作用机制并提高其对HNSCC的疗效。在本研究中，我们发现CYH33对HNSCC显示出有前景但可变的治疗活性。CYH33对PI3K/Akt通路的抑制不足以解释其对HNSCC的活性。我们进行了串联质谱标签（TMT）磷酸化蛋白质组学分析，以揭示CYH33对激酶组的全面调控。特别是，Erk磷酸化的减弱与HNSCC细胞对CYH33的敏感性相关。机制上，CYH33对PI3K的抑制阻断了PIP3的产生，并减弱了GAB1的膜定位和磷酸化，导致Erk磷酸化减少，并最终抑制敏感HNSCC细胞的增殖。同时，EGFR的激活在HNSCC细胞中诱导了与PI3K无关的GAB1磷酸化。同时抑制EGFR可协同增强CYH33对HNSCC的活性。这些发现揭示了CYH33抗HNSCC的内在机制，并为HNSCC治疗提供了合理的联合用药方案。
