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Restraining Network Response to Targeted Cancer Therapies Improves Efficacy and Reduces Cellular Resistance

Tirtha K Das1, Jessica Esernio2, Ross L Cagan2

  • 1Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, New York. tirtha.das@mssm.edu.

Cancer Research
|May 31, 2018
PubMed

Insights

Targeted cancer therapies can cause resistance by hyperactivating cellular networks. Combining these drugs with "network brake" inhibitors, like those targeting histone deacetylases, proteasome, or Hsp90, prevents resistance and reduces toxicity.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Targeted cancer therapies inhibiting oncogene-addicted pathways are crucial but limited by emergent drug resistance.
  • Drug resistance arises from cellular adaptation, leading to hyperactivation of cellular networks and expression of stem cell markers.

Purpose of the Study:

  • To investigate the mechanisms of emergent resistance to targeted cancer therapies using *Drosophila* as a model system.
  • To identify therapeutic strategies to overcome drug resistance and reduce toxicity associated with targeted cancer treatments.

Main Methods:

  • Treatment of *Drosophila* models with various kinase inhibitors to observe cellular responses.
  • Utilizing genetic and drug screens to identify compounds that counteract network hyperactivation.
  • Evaluating the efficacy of combination therapies involving targeted drugs and "network brake" inhibitors.

Main Results:

  • Kinase inhibitor treatment induced hyperactivation of cellular networks, leading to resistance and Sox2 expression.
  • Inhibitors of histone deacetylases, proteasome, and Hsp90 proteins effectively restrained network hyperactivation.
  • Combination therapy with "network brake" cocktails prevented resistance, promoted cell death at subtherapeutic doses, and reduced toxicity.

Conclusions:

  • Targeted therapies can induce a general resistance and toxicity response in both transformed and normal cells.
  • Pairing targeted therapeutics with subtherapeutic doses of broad-acting "network brake" drugs offers a strategy to enhance therapeutic utility and minimize systemic toxicity.
  • This approach presents an innovative strategy for developing effective combination cancer treatments.

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