Temporally sequenced anticancer drugs overcome adaptive resistance by targeting a vulnerable chemotherapy-induced phenotypic transition

Nat Commun. 2015 Feb 11;6:6139. doi: 10.1038/ncomms7139.

Abstract

Understanding the emerging models of adaptive resistance is key to overcoming cancer chemotherapy failure. Using human breast cancer explants, in vitro cell lines, mouse in vivo studies and mathematical modelling, here we show that exposure to a taxane induces phenotypic cell state transition towards a favoured transient CD44(Hi)CD24(Hi) chemotherapy-tolerant state. This state is associated with a clustering of CD44 and CD24 in membrane lipid rafts, leading to the activation of Src Family Kinase (SFK)/hemopoietic cell kinase (Hck) and suppression of apoptosis. The use of pharmacological inhibitors of SFK/Hck in combination with taxanes in a temporally constrained manner, where the kinase inhibitor is administered post taxane treatment, but not when co-administered, markedly sensitizes the chemotolerant cells to the chemotherapy. This approach of harnessing chemotherapy-induced phenotypic cell state transition for improving antitumour outcome could emerge as a translational strategy for the management of cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Bridged-Ring Compounds / pharmacology
  • Carcinogenesis / drug effects
  • Carcinogenesis / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Drug Evaluation, Preclinical
  • Drug Resistance, Neoplasm / drug effects*
  • Female
  • Humans
  • Membrane Microdomains / metabolism
  • Mice, Inbred BALB C
  • Models, Biological
  • Neoplasms / drug therapy
  • Neoplasms / pathology*
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Phenotype
  • Protein Kinase Inhibitors / pharmacology
  • Signal Transduction / drug effects
  • Taxoids / pharmacology
  • Time Factors

Substances

  • Antigens, CD
  • Antineoplastic Agents
  • Bridged-Ring Compounds
  • Protein Kinase Inhibitors
  • Taxoids
  • taxane