Genetic Variants Involved in Intracellular Mechanisms of Chemoresistance to Anticancer Drugs Due to Changes in the Effect on Their Molecular Targets

Abstract

Modern anticancer pharmacological treatment is challenged by the important limitation of the refractoriness of many tumours to anticancer drugs. This is due to different combinations of a complex and yet poorly understood variety of mechanisms of chemoresistance, which account for a reduction in the intracellular concentrations of active agents or poor response to their action. The present article focusses on changes in the expression and appearance of the genetic variants affecting genes involved in a weaker activity of the intracellular active agents, which may be accounted for by: (1) changes in the molecular targets of these drugs, either by directly reducing or enhancing the expression of the target or by modifying its ability to respond to the drug; (2) enhanced repair of drug‐induced deoxyribonucleic acid damage; and finally, because the activation of apoptosis is a final goal of many pharmacological regimes; (3) the stimulation of antiapoptotic mechanisms and/or the inhibition of proapoptotic ones.

Key Concepts:

  • Changes in the expression levels of molecular targets strongly determine the efficacy of anticancer drugs.

  • Chemoresistance may be due to the appearance of genetic variants accounting for changes in the ability of molecular targets to respond to anticancer drugs.

  • Antitumour drugs, whose mechanism of action is based on DNA damage, are less efficient in tumour cells with enhanced DNA‐repairing activity.

  • The presence of genetic variants accounting for an impaired function of proapoptotic genes favour tumour chemoresistance.

  • The presence of genetic variants accounting for a constitutive activation of survival pathways reduces the efficacy of anticancer drugs.

Keywords: apoptosis; anticancer drug; cancer; mutation; pharmacology; refractoriness; SNP

Figure 1.

Schematic representation of genes involved in MOC due to changes of expression or the appearance of genetic variants in the molecular targets of anticancer drugs.

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Marin, Jose JG, Blazquez, Alba G, Serrano, Maria A, Briz, Oscar, Monte, Maria J, and Macias, Rocio IR(Dec 2013) Genetic Variants Involved in Intracellular Mechanisms of Chemoresistance to Anticancer Drugs Due to Changes in the Effect on Their Molecular Targets. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025217]