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Tumour heterogeneity and the evolution of polyclonal drug resistance

Rebecca A Burrell1, Charles Swanton1

  • 1Translational Cancer Therapeutics Laboratory, Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3L7, UK; UCL Cancer Institute, Paul O'Gorman Building University College London, 72 Huntley Street, London WC1E 6DD, UK.

Molecular Oncology
|August 5, 2014
PubMed

Insights

Cancer drug resistance, driven by intratumour genetic heterogeneity (ITH), poses a significant challenge. Targeting single resistance mechanisms may be insufficient, necessitating studies on tumour evolution during therapy.

Area of Science:

  • Oncology
  • Genetics
  • Pharmacology

Background:

  • Multidrug resistance (MDR) is a primary cause of cancer treatment failure in metastatic disease.
  • Genomic technologies and preclinical research have improved understanding of treatment failure mechanisms.
  • Intratumour genetic heterogeneity (ITH) significantly contributes to therapeutic failure.

Purpose of the Study:

  • To highlight the role of ITH and polyclonal resistance in cancer treatment failure.
  • To emphasize the limitations of targeting single resistance mechanisms.
  • To advocate for clinical studies analyzing tumour evolution during therapy.

Main Methods:

  • Review of current understanding of molecular events in cancer drug resistance.
  • Analysis of the impact of intratumour genetic heterogeneity (ITH).
  • Discussion of preclinical and clinical findings related to therapeutic failure.

Main Results:

  • ITH enables tumours to develop resistance through multiple simultaneous routes (polyclonal resistance).
  • Targeting individual resistance mechanisms may offer limited clinical benefit.
  • Tumour evolution and inter-clonal dynamics during therapy are critical factors.

Conclusions:

  • Understanding polyclonal resistance is crucial for overcoming cancer drug resistance.
  • Sequential analysis of tumour material in clinical studies is needed.
  • Improved drug development strategies require insights into tumour evolution and resistance mechanisms.
Keywords:
Cancer evolutionDrug resistanceGenomic instabilityIntratumour heterogeneity

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