Cooperative Targets of Combined mTOR/HDAC Inhibition Promote MYC Degradation

Molecular Cancer Therapeutics
John K SimmonsBeverly A Mock

Abstract

Cancer treatments often require combinations of molecularly targeted agents to be effective. mTORi (rapamycin) and HDACi (MS-275/entinostat) inhibitors have been shown to be effective in limiting tumor growth, and here we define part of the cooperative action of this drug combination. More than 60 human cancer cell lines responded synergistically (CI<1) when treated with this drug combination compared with single agents. In addition, a breast cancer patient-derived xenograft, and a BCL-XL plasmacytoma mouse model both showed enhanced responses to the combination compared with single agents. Mice bearing plasma cell tumors lived an average of 70 days longer on combination treatment compared with single agents. A set of 37 genes cooperatively affected (34 downregulated; 3 upregulated) by the combination responded pharmacodynamically in human myeloma cell lines, xenografts, and a P493 model, and were both enriched in tumors, and correlated with prognostic markers in myeloma patient datasets. Genes downregulated by the combination were overexpressed in several untreated cancers (breast, lung, colon, sarcoma, head and neck, myeloma) compared with normal tissues. The MYC/E2F axis, identified by upstream regulator analyses and validat...Continue Reading

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Citations

Jan 20, 2018·Cancers·Fabiana ConciatoriMichele Milella
May 30, 2020·International Journal of Molecular Sciences·Jochen RutzBorna Relja
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Aug 5, 2020·Molecular Cancer Therapeutics·Joy M GaryBeverly A Mock
Nov 19, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Matthew D HellmannPeter Ordentlich
Jun 18, 2021·Bioorganic & Medicinal Chemistry Letters·Dahong YaoJinhui Wang

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