Targeting intrinsic and CAF-mediated signaling by PI3Kα inhibitor CYH33 attenuated metastasis in lung squamous cell carcinoma
文献类型：期刊论文
| 作者 | Ma, Xiao-yu1,2; Deng, Jie-ting2,4; Cao, Zhe-rui2,4; Xu, Lan2; Ding, Jian3; Meng, Ling-hua1,2,4 |
| 刊名 | ACTA PHARMACOLOGICA SINICA
 |
| 出版日期 | 2026-01-16 |
| 页码 | 14 |
| 关键词 | LUSC CYH33 PI3K alpha CAF metastasis |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/s41401-025-01719-z |
| 英文摘要 | Aberrant activation of PI3K signaling is frequently observed in lung squamous cell carcinoma (LUSC) and is strongly associated with metastasis in advanced-stage patients, but the therapeutic efficacy of PI3K inhibitors and underlying mechanisms in LUSC remain poorly defined. CYH33 is a highly selective PI3K alpha inhibitor, which is in phase I/II clinical trials for the therapy of advanced solid tumors including LUSC. In this study, we investigated the efficacy of CYH33 against metastatic LUSC. We showed that CYH33 dose-dependently suppressed the motility of LUSC cells by blocking PI3K signaling and disrupting cytoskeletal structure. Oral administration of CYH33 significantly attenuated the metastasis of orthotopically implanted xenografts derived from LUSC SK-MES-1 cells. RNA-seq and GO enrichment analysis revealed that CYH33 treatment resulted in decreased infiltration of cancer-associated fibroblasts (CAFs) in primary tumors. We demonstrated that CAFs promoted the migration of SK-MES-1 cells by secreting the pro-migratory factors and activating PI3K signaling in tumor cells, which was blocked by CYH33. Moreover, CYH33 concurrently suppressed the trans-differentiation and proliferation of CAFs, thereby reducing the secretion of hepatocyte growth factor (HGF), which likely contributed to its anti-metastatic effect. Consistently, co-inoculation of SK-MES-1 cells with fibroblasts significantly potentiated tumor metastasis in nude mice, whereas CYH33 treatment robustly suppressed this process, accompanied with reduced expression of alpha-SMA and HGF as well as epithelial-mesenchymal transition (EMT) signature in primary tumor. Furthermore, CYH33 possessed potent activity against the growth of LUSC with hyperactivated PI3K signaling. Collectively, the dual-targeting of CYH33 that directly blocked PI3K alpha in tumor cells and disrupted CAF-mediated pro-metastatic signaling supported PI3K alpha inhibitors as a potential therapeutic approach for advanced LUSC. |
| WOS关键词 | CANCER-ASSOCIATED FIBROBLASTS ; MIGRATION ; INVASION ; PROMOTES ; PATHWAY |
| 资助项目 | Strategic Priority Research Program of the Chinese Academy of Sciences[XDB1060000] ; National Natural Science Foundation of China[82173832] ; Science and Technology Commission of Shanghai Municipality[24ZR1477700] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001662291000001 |
| 出版者 | NATURE PUBL GROUP |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/322631]  |
| 专题 | 国家级研究中心_原创新药研究全国重点实验室 |
| 通讯作者 | Meng, Ling-hua |
| 作者单位 | 1.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Chem Biol, Shanghai 201203, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China 4.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China |
| 推荐引用方式 GB/T 7714 | Ma, Xiao-yu,Deng, Jie-ting,Cao, Zhe-rui,et al. Targeting intrinsic and CAF-mediated signaling by PI3Kα inhibitor CYH33 attenuated metastasis in lung squamous cell carcinoma[J]. ACTA PHARMACOLOGICA SINICA,2026:14. |
| APA | Ma, Xiao-yu,Deng, Jie-ting,Cao, Zhe-rui,Xu, Lan,Ding, Jian,&Meng, Ling-hua.(2026).Targeting intrinsic and CAF-mediated signaling by PI3Kα inhibitor CYH33 attenuated metastasis in lung squamous cell carcinoma.ACTA PHARMACOLOGICA SINICA,14. |
| MLA | Ma, Xiao-yu,et al."Targeting intrinsic and CAF-mediated signaling by PI3Kα inhibitor CYH33 attenuated metastasis in lung squamous cell carcinoma".ACTA PHARMACOLOGICA SINICA (2026):14. |
入库方式： OAI收割
来源：上海药物研究所
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