CCN1 is a therapeutic target upregulated in EML4-ALK mutant lung adenocarcinoma reversibly resistant to alectinib

被引：0

作者：

Yihua Huang ^{[1
]}

Jie Huang ^{[2
]}

Jianhua Zhan ^{[1
]}

Maojian Chen ^{[1
]}

Jiani Zheng ^{[3
]}

Junyi He ^{[4
]}

Wenfeng Fang ^{[1
]}

Li Zhang ^{[1
]}

Jing Li ^{[1
]}

机构：

[1] Department of Medical Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Sun Yat-sen University, Guangzhou

[2] Phase I Clinical Trial Centre, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou

[3] Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou

[4] Department of Medical Oncology, Xiamen Key Laboratory of Antitumor Drug Transformation Research, the First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen

来源：

Cell Death & Disease | / 16卷 / 1期

关键词：

D O I：

10.1038/s41419-025-07601-4

中图分类号：

学科分类号：

摘要：

There is limited understanding of the phenomenon of reversible drug resistance, which is characterized by tumor cells regaining sensitivity when the drug is changed or withdrawn after a period of drug resistance. This phenomenon is usually not associated with genetic alterations of tumor cells. In this study, reversible resistant state was induced by alectinib in EML4-ALK mutant lung cancer cell. By performing RNA sequencing on reversible drug-resistant cell line to examine changes in transcriptional profile, significant change in CCN1 was detected after withdrawal and repeated administration of alectinib. Targeting CCN1 resulted in inhibition of tumor cell proliferation and angiogenesis, and restoration of sensitivity to alectinib in reversible drug-resistant cells. Further studies revealed that CCN1 could affect the expression of VEGFA by affecting AKT phosphorylation, and the change of NF-κB could impact the activation of CCN1-AKT-VEGFA pathway. Suppressing NF-κB or CCN1 receptor could improve the sensitivity to alectinib, further suggesting that NF-κB and CCN1 might play a key role in overcoming reversible drug resistance. © The Author(s) 2025.

引用

共 44 条

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