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Updated: Feb 19, 2026

Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down
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Combating subclonal evolution of resistant cancer phenotypes

Samuel W Brady1,2, Jasmine A McQuerry1,3, Yi Qiao4

  • 1Department of Pharmacology and Toxicology, College of Pharmacy, University of Utah, 30 South 2000 East, Salt Lake City, UT, 84112, USA.

Nature Communications
|November 3, 2017
PubMed

Insights

Breast cancer cells evolve phenotypically to resist treatment, not just genetically. Targeting these acquired traits shows promise for adaptive cancer therapy.

Area of Science:

  • Cancer Biology
  • Genomics
  • Translational Oncology

Background:

  • Metastatic breast cancer treatment is limited by acquired drug resistance.
  • Tumor heterogeneity and drug-refractory subclones drive treatment failure.
  • Understanding subclonal evolution is critical for improving therapeutic strategies.

Purpose of the Study:

  • To investigate the genetic and phenotypic evolution of breast cancer subclones during treatment.
  • To identify mechanisms of acquired drug resistance in metastatic breast cancer.
  • To evaluate the potential of phenotype-targeted therapies for overcoming resistance.

Main Methods:

  • Longitudinal tracking of genetic and phenotypic subclonal evolution in four breast cancer patients.
  • Utilized bulk and single-cell RNA sequencing to analyze tumor changes over time.
  • Assessed the impact of chemotherapy on subclone dominance and gene expression profiles.

Main Results:

  • Acquired genetic mutations post-chemotherapy were rare.
  • Significant phenotypic changes were observed, including enhanced mesenchymal and growth factor signaling, and decreased antigen presentation and TNF-α signaling.
  • Pre-existing subclones with resistant phenotypes were selected for by chemotherapy, indicating adaptive evolution.

Conclusions:

  • Breast cancer exhibits phenotypic evolution as a key mechanism of drug resistance.
  • Acquired malignant phenotypes can be targeted by specific therapies, showing effectiveness in post-chemotherapy cells.
  • An adaptive, phenotype-targeted treatment strategy is proposed to combat evolving cancer resistance.

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