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Drug resistance in the mouse cancer clinic

Sven Rottenberg1, Piet Borst

  • 1Division of Molecular Biology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. s.rottenberg@nki.nl

Drug Resistance Updates : Reviews and Commentaries in Antimicrobial and Anticancer Chemotherapy
|February 17, 2012
PubMed

Insights

Genetically engineered mouse models (GEMMs) help study cancer drug resistance. These models show how DNA repair defects impact chemotherapy sensitivity and reveal mechanisms of resistance, bridging the gap between lab findings and patient outcomes.

Area of Science:

  • Oncology
  • Cancer Biology
  • Genetics

Background:

  • Drug resistance is a major challenge in cancer therapy, leading to treatment failure and patient mortality from distant metastases.
  • Translating findings from cell lines to clinical drug resistance in patients remains difficult, with ongoing debate about mechanisms like ABC transporters.
  • Genetically engineered mouse models (GEMMs) offer a promising approach to study cancer, closely mimicking human disease and aiding the translation of research findings.

Purpose of the Study:

  • To review the utility of next-generation mouse models in addressing critical clinical challenges in cancer drug resistance.
  • To explore mechanisms of chemotherapy resistance, predict patient response to treatment, and characterize residual tumor cells.
  • To investigate the role of ABC transporters in drug resistance within these advanced mouse models.

Main Methods:

  • Utilizing genetically engineered mouse models (GEMMs) that closely recapitulate human cancers, particularly BRCA1/2-associated breast cancer.
  • Observing the synergy between defects in homology-directed DNA repair and sensitivity to DNA-targeting chemotherapy agents.
  • Analyzing drug resistance development and progression in these models to understand clinical challenges.

Main Results:

  • GEMMs demonstrate a significant interplay between DNA repair deficiencies and sensitivity to DNA-damaging drugs.
  • Tumor eradication remains challenging, with drug resistance inevitably developing over time in these models.
  • The study provides insights into mechanisms of drug resistance and the potential contribution of ABC transporters.

Conclusions:

  • Next-generation GEMMs are valuable tools for dissecting complex clinical problems in cancer drug resistance.
  • These models facilitate the study of chemotherapy response prediction and the characterization of treatment-refractory tumor cells.
  • Further investigation using GEMMs can elucidate the role of specific mechanisms, such as ABC transporters, in clinical drug resistance.

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