Drug resistance in cancer: an overview

Abstract

Cancers have the ability to develop resistance to traditional therapies, and the increasing prevalence of these drug resistant cancers necessitates further research and treatment development. This paper outlines the current knowledge of mechanisms that promote or enable drug resistance, such as drug inactivation, drug target alteration, drug efflux, DNA damage repair, cell death inhibition, and the epithelial-mesenchymal transition, as well as how inherent tumor cell heterogeneity plays a role in drug resistance. It also describes the epigenetic modifications that can induce drug resistance and considers how such epigenetic factors may contribute to the development of cancer progenitor cells, which are not killed by conventional cancer therapies. Lastly, this review concludes with a discussion on the best treatment options for existing drug resistant cancers, ways to prevent the formation of drug resistant cancers and cancer progenitor cells, and future directions of study.

Figure 1

Categories of mechanisms that can enable or promote direct or indirect drug resistance in human cancer cells. These mechanisms can act independently or in combination and through various signal transduction pathways.

Figure 2

Depiction of the primary mechanisms that enable cancer cells to become drug resistant. These include drug inactivation, alteration of drug targets, drug efflux, DNA damage repair, inhibition of cell death, EMT, and epigenetic effects. In the case of EMT, stromal cells assist in this process and signal for improved drug resistance in cancer cells. Cell adhesion molecules on stromal cells and extracellular matrix proteins attach to the cell adhesion molecules on cancer cells. Stromal cells and cancer cells also secrete factors that regulate EMT. The depiction displays a simplified example of these cell interactions.