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

J Pharmacol Exp Ther. 2019 Nov;371(2):320-326. doi: 10.1124/jpet.119.258392. Epub 2019 Aug 27.

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. SIGNIFICANCE STATEMENT: In this article, we report our findings on the potential mechanism of resistance to CC-115, a dual inhibitor of mTOR and DNA-PK currently in clinical trials. We show that CC-115 is a substrate of ABCG2 and can be recognized by ABCB1, which contributes to CC-115 resistance. These findings provide novel information and potential guidance on future clinical testing of CC-115.

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B / metabolism
  • ATP Binding Cassette Transporter, Subfamily G, Member 2 / metabolism*
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Clinical Trials as Topic / methods
  • DNA / antagonists & inhibitors
  • DNA / metabolism
  • Dose-Response Relationship, Drug
  • Drug Resistance / drug effects*
  • Drug Resistance / physiology
  • HEK293 Cells
  • Humans
  • MCF-7 Cells
  • Neoplasm Proteins / metabolism*
  • Protein Kinase Inhibitors / pharmacology*
  • Pyrazines / pharmacology*
  • Risk Factors
  • Substrate Specificity / drug effects
  • Substrate Specificity / physiology
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / metabolism*
  • Triazoles / pharmacology*

Substances

  • ABCB1 protein, human
  • ABCG2 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily G, Member 2
  • Neoplasm Proteins
  • Protein Kinase Inhibitors
  • Pyrazines
  • Triazoles
  • DNA
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • 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