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A network-based phenotype mapping approach to identify genes that modulate drug response phenotypes

Junmei Cairns1, Choong Yong Ung1, Edroaldo Lummertz da Rocha1

  • 1Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.

Scientific Reports
|November 15, 2016
PubMed

Insights

Scientists developed a network-based approach (P-Map) to identify genes that alter cancer drug sensitivity. Perturbing these genes can switch drug response phenotypes, offering new therapeutic strategies for drug resistance.

Area of Science:

  • Genomics
  • Systems Biology
  • Pharmacology

Background:

  • Drug resistance is a major challenge in cancer chemotherapy.
  • Understanding and manipulating drug response phenotypes is crucial for effective treatment.

Purpose of the Study:

  • To develop a network-based approach (P-Map) for identifying gene candidates that can alter drug sensitivity.
  • To explore the possibility of manipulating drug response phenotypes in cancer cells.
  • To identify potential targets for overcoming drug resistance.

Main Methods:

  • Utilized basal transcriptomics data from human lymphoblastoid cell lines (LCL).
  • Inferred drug response networks (DRNs) for anthracycline and taxane response phenotypes.
  • Tested selected gene candidates interacting with phenotypic differentially expressed genes (PDEGs) in triple-negative breast cancer (TNBC) cells.

Main Results:

  • Demonstrated that perturbing gene candidates in DRNs can alter drug response phenotypes (resistant to sensitive, or vice versa).
  • Identified plausible mechanisms regulating the directionality of drug response sensitivity.
  • Validated the approach in TNBC cells.

Conclusions:

  • The P-Map approach offers a novel strategy for identifying genes that modulate cancer drug sensitivity.
  • Perturbing identified gene candidates can potentially reverse drug resistance phenotypes.
  • This work highlights a new direction for systems-based therapeutic design, focusing on phenotypic modulators to re-sensitize resistant cancers.

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