CCN1 is a therapeutic target upregulated in EML4-ALK mutant lung adenocarcinoma reversibly resistant to alectinib
Abstract 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of reversible drug resistance, which is characterized by tumor cells regaining sensitivity when the drug is changed or withdrawn after a period of drug resistance.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 ce...
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| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2025-04-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07601-4 |
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| Summary: | Abstract 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of reversible drug resistance, which is characterized by tumor cells regaining sensitivity when the drug is changed or withdrawn after a period of drug resistance.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. |
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| ISSN: | 2041-4889 |