Restraining Network Response to Targeted Cancer Therapies Improves Efficacy and Reduces Cellular Resistance
Abstract
A key tool of cancer therapy has been targeted inhibition of oncogene-addicted pathways. However, efficacy has been limited by progressive emergence of resistance as transformed cells adapt. Here, we use Drosophila to dissect response to targeted therapies. Treatment with a range of kinase inhibitors led to hyperactivation of overall cellular networks, resulting in emergent resistance and expression of stem cell markers, including Sox2. Genetic and drug screens revealed that inhibitors of histone deacetylases, proteasome, and Hsp90 family of proteins restrained this network hyperactivation. These “network brake” cocktails, used as adjuncts, prevented emergent resistance and promoted cell death at subtherapeutic doses. Our results highlight a general response of cells, transformed and normal, to targeted therapies that leads to resistance and toxicity. Pairing targeted therapeutics with subtherapeutic doses of broad-acting “network brake” drugs may provide a means of extending therapeutic utility while reducing whole body toxicity.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 31, 2018
- Source ID
- 10.1158/0008-5472.can-17-2001
Entities
People
- Jessica Esernio
- Ross Cagan
- Tirtha K. Das
Organizations
- American Cancer Society
- Icahn School of Medicine at Mount Sinai
- National Institutes of Health
- United States Department of Defense