Mechanisms and insights into drug resistance in cancer

Abstract

Cancer drug resistance continues to be a major impediment in medical oncology. Clinically, resistance can arise prior to or as a result of cancer therapy. In this review, we discuss different mechanisms adapted by cancerous cells to resist treatment, including alteration in drug transport and metabolism, mutation and amplification of drug targets, as well as genetic rewiring which can lead to impaired apoptosis. Tumor heterogeneity may also contribute to resistance, where small subpopulations of cells may acquire or stochastically already possess some of the features enabling them to emerge under selective drug pressure. Making the problem even more challenging, some of these resistance pathways lead to multidrug resistance, generating an even more difficult clinical problem to overcome. We provide examples of these mechanisms and some insights into how understanding these processes can influence the next generation of cancer therapies.

Keywords: collateral sensitivity; drug metabolism; drug transporters; microenvironment; multidrug resistance; oncogene addiction; origin of cancer; synthetic lethality.

FIGURE 1

A major impediment in the treatment of cancer is the development of resistance. While most tumors initially respond to the given therapy, the majority will relapse following treatment, and in some cases resistance even predates clinical intervention. Therefore cancer resistance can be classified in to two broad classes: primary or acquired. In both cases, the emergence of resistant cells could be due to, at least, two mechanisms: (A) presence of multiple initial clones some of which emerge as dominant after treatment. These subpopulations could possess stem-like characteristics and/or use their interactions with the surrounding microenvironment to enter into a dormant state, thus surviving the insult of therapy. (B) Acquisition of stochastic alterations within the cancer cells per se. In all cases, the surviving population is less likely to respond to any further therapy and will be responsible for the minimal residual disease and cancer relapse. The biochemical underpinnings of resistance include: alterations to drug metabolism, increased drug efflux, decreased drug uptake, modification of the drug targets, amplification of targeted protein, genetic rewiring, enhanced DNA repair, inactivation of apoptotic proteins, or activation of anti-apoptotic ones, among others.