Why drug resistance occurs in cancer therapies

You must have heard about  drug resistance with regard to bacteria. But have you heard about drug resistance to cancer chemotherapy?

Yes, Cancers have the ability to develop resistance to traditional therapies.

Anticancer drugs resistance is a complex process that arises from altering in the drug targets. Advances in the DNA microarray, proteomics technology and the development of targeted therapies provide the new strategies to overcome the drug resistance. Although a design of the new chemotherapy agents is growing quickly, effective chemotherapy agent has not been discovered against the advanced stage of cancer (such as invasion and metastasis). The cancer cell resistance against the anticancer agents can be due to many factors such as the individual’s genetic differences, especially in tumoral somatic cells,( inherent tumour cell heterogeneity). Also, the cancer drug resistance is acquired, the drug resistance can be occurred by different mechanisms, including multi-drug resistance achieved by  drug inactivation, drug target alteration, drug efflux, cell death inhibiting (apoptosis suppression), and the epithelial-mesenchymal transition, altering in the drug metabolism, epigenetic modifications and drug targets, enhancing DNA repair and gene amplification. 

This image gives an overall picture of cancer drug resistance...

Drug activation in people involves complex mechanisms in which substances interact with different proteins. These interactions can modify, partially degrade, or complex the drug with other molecules or proteins, ultimately leading to its activation. Many anticancer drugs must undergo metabolic activation in order to acquire clinical efficacy. Many anticancer drugs require metabolic activation, and thus cancer cells can develop resistance through decreased drug activation. 

A drug’s efficacy is influenced by its molecular target and alterations of this target, such as mutations or modifications of expression levels. In cancers, these types of target alterations can ultimately lead to drug resistance. Modified enzyme expression levels at drug target sites can also alter drug responses in cancer cells. In addition to the changes in specific drug targets, drug resistance is also achieved by alteration in the signal transduction process that mediates drug activation. Alterations in signaling mechanisms also affect drugs efficiency.

Drug efflux is one of the most studied mechanisms of cancer drug resistance involves reducing drug accumulation by enhancing efflux ( draining out). Some proteins in cells remove these drugs and take them out of cancer cells  and protect them from many first line chemotherapies. 

The repair of damaged DNA has a clear role in anticancer drug resistance. In response to chemotherapy drugs that either directly or indirectly damage DNA, DNA damage response (DDR) mechanisms can reverse the drug-induced damage. 

Cell death by apoptosis and autophagy are two important regulatory events that contribute to cell death. Some drugs are used to kill cancer cells  by taking these two regulatory mechanisms but prolonged use can produce resistance.