PI3K-dependent GAB1/Erk phosphorylation renders head and neck squamous cell carcinoma sensitive to PI3Kα inhibitors
文献类型：期刊论文
| 作者 | Zhang, Xu7; Xu, Jiao5,6,7; Wang, Xuan4,7; Xu, Lan7; Zhang, Xi7; Wang, Yi7; Jiang, Shujuan3; Zhang, Yixiang3; Ding, Jian1,2,4 ; Qing, Chen5,6
|
| 刊名 | CELL DEATH & DISEASE
 |
| 出版日期 | 2025-06-18 |
| 卷号 | 16期号:1页码:13 |
| ISSN号 | 2041-4889 |
| DOI | 10.1038/s41419-025-07767-x |
| 英文摘要 | 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 PI3K alpha-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. |
| WOS关键词 | PLECKSTRIN HOMOLOGY DOMAIN ; PHOSPHATIDYLINOSITOL 3-KINASE ; SCAFFOLDING PROTEIN ; DOCKING PROTEIN ; PHASE-I ; CANCER ; CONTRIBUTES ; DOWNSTREAM ; REVEALS ; MET |
| 资助项目 | National Natural Science Foundation of China[82173832] ; National Natural Science Foundation of China[82404656] ; Science and Technology Commission of Shanghai Municipality[24ZR1477700] ; Science and Technology Commission of Shanghai Municipality[22ZR1474400] ; State Key Laboratory of Chemical Biology and the Strategic Priority Research Program of the Chinese Academy of Sciences[XDB1060000] ; Postdoctoral Excellence Program of Shanghai[2023710] ; Postdoctoral Fellowship Program of CPSF[GZC20232841] |
| WOS研究方向 | Cell Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:001512195100001 |
| 出版者 | SPRINGERNATURE |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/318657]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Ding, Jian; Qing, Chen; Meng, Linghua |
| 作者单位 | 1.Univ Chinese Acad Sci, Beijing, Peoples R China 2.Chinese Acad Sci, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai, Peoples R China 3.Haihe Biopharm Co Ltd, Shanghai, Peoples R China 4.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China 5.Kunming Med Univ, Yunnan Key Lab Pharmacol Nat Prod, Kunming, Yunnan, Peoples R China 6.Kunming Med Univ, Sch Pharmaceut Sci, Kunming, Yunnan, Peoples R China 7.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Chem Biol, Shanghai, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhang, Xu,Xu, Jiao,Wang, Xuan,et al. PI3K-dependent GAB1/Erk phosphorylation renders head and neck squamous cell carcinoma sensitive to PI3Kα inhibitors[J]. CELL DEATH & DISEASE,2025,16(1):13. |
| APA | Zhang, Xu.,Xu, Jiao.,Wang, Xuan.,Xu, Lan.,Zhang, Xi.,...&Meng, Linghua.(2025).PI3K-dependent GAB1/Erk phosphorylation renders head and neck squamous cell carcinoma sensitive to PI3Kα inhibitors.CELL DEATH & DISEASE,16(1),13. |
| MLA | Zhang, Xu,et al."PI3K-dependent GAB1/Erk phosphorylation renders head and neck squamous cell carcinoma sensitive to PI3Kα inhibitors".CELL DEATH & DISEASE 16.1(2025):13. |
入库方式： OAI收割
来源：上海药物研究所
浏览0
下载0
收藏0
其他版本
除非特别说明，本系统中所有内容都受版权保护，并保留所有权利。