Targeting an Inducible SALL4-Mediated Cancer Vulnerability with Sequential Therapy
| Autor: | Jianzhong Xi, Miao Liu, Yue Wu, Hannan Wong, Shenyi Yin, Hongbo R. Luo, Xi Tian, Alicia Stein, Julie A. I. Thoms, Yanjing V. Liu, Zhiyuan Chen, John E. Pimanda, Leslie E. Silberstein, Daniel G. Tenen, Kalpana Kumari, Nikki R. Kong, Jun Qi, Junyu Yang, Chong Gao, Yao-Chung Liu, Junsu Kwon, Li Chai, Ashwin Unnikrishnan |
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| Rok vydání: | 2021 |
| Předmět: |
Cancer Research
Pyridines Apoptosis Mice SCID Decitabine Article Mice chemistry.chemical_compound Downregulation and upregulation Mice Inbred NOD SALL4 Neoplasms Antineoplastic Combined Chemotherapy Protocols microRNA Tumor Cells Cultured Animals Humans Medicine Cell Proliferation business.industry Entinostat Cancer DNA Methylation medicine.disease Xenograft Model Antitumor Assays eye diseases Gene Expression Regulation Neoplastic Oncology chemistry Hypomethylating agent Benzamides Cancer cell Cancer research Deoxycytidine business Transcription Factors |
| Zdroj: | Cancer Res |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-21-0030 |
| Popis: | Oncofetal protein SALL4 is critical for cancer cell survival. Targeting SALL4, however, is only applicable in a fraction of cancer patients who are positive for this gene. To overcome this limitation, we propose to induce a cancer vulnerability by engineering a partial dependency upon SALL4. Following exogenous expression of SALL4, SALL4-negative cancer cells became partially dependent on SALL4. Treatment of SALL4-negative cells with the FDA-approved hypomethylating agent 5-aza-2′-deoxycytidine (DAC) resulted in transient upregulation of SALL4. DAC pretreatment sensitized SALL4-negative cancer cells to entinostat, which negatively affected SALL4 expression through a microRNA, miRNA-205, both in culture and in vivo. Moreover, SALL4 was essential for the efficiency of sequential treatment of DAC and entinostat. Overall, this proof-of-concept study provides a framework whereby the targeting pathways such as SALL4-centered therapy can be expanded, sensitizing cancer cells to treatment by transient target induction and engineering a dependency. Significance: These findings provide a therapeutic approach for patients harboring no suitable target by induction of a SALL4-mediated vulnerability. |
| Databáze: | OpenAIRE |
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