CC-115, a dual mammalian target of rapamycin/ DNA-dependent protein kinase inhibitor in clinical trial, is a substrate of ATP-binding cassette G2, a risk factor for CC-115 resistance

Jenny Beebe, Jian Ting Zhang

Research output: Contribution to journalArticle

Abstract

CC-115, a triazole-containing compound, is a dual mammalian target of rapamycin (mTOR)/DNA-dependent protein kinase (DNA-PK) inhibitor currently in clinical trials. To develop this compound further, we investigated factors that may affect cellular response to CC-115. Previously, fatty acid synthase (FASN) was shown to upregulate DNA-PK activity and contribute to drug resistance; therefore, we hypothesized that FASN may affect cellular response to CC-115. Instead, however, we showed that CC-115 is a substrate of ATP-binding cassette G2 (ABCG2), a member of the ATP-binding cassette transporter superfamily, and that expression of ABCG2, not FASN, affects the potency of CC-115. ABCG2 overexpression significantly increases resistance to CC-115. Inhibiting ABCG2 function, using small-molecule inhibitors, sensitizes cancer cells to CC-115. We also found that CC-115 may be a substrate of ABCB1, another known ABC protein that contributes to drug resistance. These findings suggest that expression of ABC transporters, including ABCB1 and ABCG2, may affect the outcome in clinical trials testing CC-115. Additionally, the data indicate that ABC transporters may be used as markers for future precision use of CC-115.

Original languageEnglish (US)
Pages (from-to)320-326
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume371
Issue number2
DOIs
StatePublished - Jan 1 2019

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DNA-Activated Protein Kinase
Sirolimus
Protein Kinase Inhibitors
Adenosine Triphosphate
Clinical Trials
Fatty Acid Synthases
ATP-Binding Cassette Transporters
Drug Resistance
1-ethyl-7-(2-methyl-6-(1H-1,2,4-triazol-3-yl)pyridin-3-yl)-3,4-dihydropyrazino(2,3-b)pyrazin-2(1H)-one
Triazoles
Up-Regulation

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

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title = "CC-115, a dual mammalian target of rapamycin/ DNA-dependent protein kinase inhibitor in clinical trial, is a substrate of ATP-binding cassette G2, a risk factor for CC-115 resistance",
abstract = "CC-115, a triazole-containing compound, is a dual mammalian target of rapamycin (mTOR)/DNA-dependent protein kinase (DNA-PK) inhibitor currently in clinical trials. To develop this compound further, we investigated factors that may affect cellular response to CC-115. Previously, fatty acid synthase (FASN) was shown to upregulate DNA-PK activity and contribute to drug resistance; therefore, we hypothesized that FASN may affect cellular response to CC-115. Instead, however, we showed that CC-115 is a substrate of ATP-binding cassette G2 (ABCG2), a member of the ATP-binding cassette transporter superfamily, and that expression of ABCG2, not FASN, affects the potency of CC-115. ABCG2 overexpression significantly increases resistance to CC-115. Inhibiting ABCG2 function, using small-molecule inhibitors, sensitizes cancer cells to CC-115. We also found that CC-115 may be a substrate of ABCB1, another known ABC protein that contributes to drug resistance. These findings suggest that expression of ABC transporters, including ABCB1 and ABCG2, may affect the outcome in clinical trials testing CC-115. Additionally, the data indicate that ABC transporters may be used as markers for future precision use of CC-115.",
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