Targeting an Inducible SALL4-Mediated Cancer Vulnerability with Sequential Therapy.
Cancer Res
; 81(23): 6018-6028, 2021 12 01.
Article
en En
| MEDLINE
| ID: mdl-34593523
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 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.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Factores de Transcripción
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Protocolos de Quimioterapia Combinada Antineoplásica
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Regulación Neoplásica de la Expresión Génica
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Metilación de ADN
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Neoplasias
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Humans
Idioma:
En
Revista:
Cancer Res
Año:
2021
Tipo del documento:
Article