Targeting an Inducible SALL4-Mediated Cancer Vulnerability with Sequential Therapy

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Abstract

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 FDAapproved hypomethylating agent 5-aza-20-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. _2021 American Association for Cancer Research.

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Yang, J., Gao, C., Liu, M., Liu, Y. C., Kwon, J., Qi, J., … Chai, L. (2021). Targeting an Inducible SALL4-Mediated Cancer Vulnerability with Sequential Therapy. Cancer Research, 81(23), 6018–6028. https://doi.org/10.1158/0008-5472.CAN-21-0030

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