Resistance mechanism in Adapted Cells to Cancer Drugs

Abstract

Background: One obstacle to greater success with chemotherapy treatment is drug resistance. Patients receiving chemotherapy become adapted to previously effective drugs and no longer respond to the effects of drugs. This is due to an evolutionary process, whereby cancer cells accumulate mutations randomly and the ones with mutations causing resistance will prevail during drug treatment through simple Darwinian selection. It is a daunting challenge to predict how genetic adaptation will occur and which adaptive mutations are likely to arise and become fixed during selection. The challenges are less formidable if using model systems that lend themselves to analysis of the mutational and selective process. Therefore, to study evolutionary adaptation in response to controlled selective pressures, a unique opportunity has been provided by experimental evolution of yeast populations. Results: A strain of Saccharomyces cerevisiae was evolved for 200 generations during exposure to four anti-cancer drugs. Three of these are mutagenic and the remaining one, rapamycin, inhibits the TOR signaling pathway. The drugs were applied both in single treatments and in all pair-wise combinations. Four replicate populations of each treatment were phenotyped by Bioscreen analyser C and promising results obtained from three growth variables; adaptation time, doubling time and growth efficiency. Also, the viability of founder strain and evolved populations under selective pressure was measured by drop test. The results of drop test show no significant difference between founder strain and the last generation of adapted populations in case of survival. Conclusions: In general adaptation occurs faster in single treatments than pair-wise treatments. In pair-wise treatment the mode of adaptation depends on the combination of drugs. It can be rapid and strong or slow and weak. Variability between populations is low, suggesting few allowed evolutionary paths. Survival has not been changed whereas proliferation and efficiency have been affected.