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Application of a Biphasic Mathematical Model of Cancer Cell Drug Response for Formulating Potent and Synergistic Targeted Drug Combinations to Triple Negative Breast Cancer Cells.
Shen, Jinyan; Li, Li; Howlett, Niall G; Cohen, Paul S; Sun, Gongqin.
Afiliación
  • Shen J; Department of Cell and Molecular Biology, University of Rhode Island, Kingston, RI 02881, USA.
  • Li L; Department of Biochemistry and Molecular Biology, Shanxi Medical University, Taiyuan 030001, China.
  • Howlett NG; Department of Cell and Molecular Biology, University of Rhode Island, Kingston, RI 02881, USA.
  • Cohen PS; Department of Cell Biology and Medical Genetics, Shanxi Medical University, Taiyuan 030001, China.
  • Sun G; Department of Cell and Molecular Biology, University of Rhode Island, Kingston, RI 02881, USA.
Cancers (Basel) ; 12(5)2020 Apr 27.
Article en En | MEDLINE | ID: mdl-32349331
ABSTRACT
Triple negative breast cancer is a collection of heterogeneous breast cancers that are immunohistochemically negative for estrogen receptor, progesterone receptor, and ErbB2 (due to deletion or lack of amplification). No dominant proliferative driver has been identified for this type of cancer, and effective targeted therapy is lacking. In this study, we hypothesized that triple negative breast cancer cells are multi-driver cancer cells, and evaluated a biphasic mathematical model for identifying potent and synergistic drug combinations for multi-driver cancer cells. The responses of two triple negative breast cancer cell lines, MDA-MB-231 and MDA-MB-468, to a panel of targeted therapy drugs were determined over a broad range of concentrations. The analyses of the drug responses by the biphasic mathematical model revealed that both cell lines were indeed dependent on multiple drivers, and inhibitors of individual drivers caused a biphasic response a target-specific partial inhibition at low nM concentrations, and an off-target toxicity at µM concentrations. We further demonstrated that combinations of drugs, targeting each driver, cause potent, synergistic, and cell-specific cell killing. Immunoblotting analysis of the effects of the individual drugs and drug combinations on the signaling pathways supports the above conclusion. These results support a multi-driver proliferation hypothesis for these triple negative breast cancer cells, and demonstrate the applicability of the biphasic mathematical model for identifying effective and synergistic targeted drug combinations for triple negative breast cancer cells.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Idioma: En Revista: Cancers (Basel) Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Idioma: En Revista: Cancers (Basel) Año: 2020 Tipo del documento: Article País de afiliación: Estados Unidos