New mechanisms explain cancer drug resistance
by the discovery of new mechanisms, which delve deeper into how
cancer cells evolve to become resistant to various chemotherapy
drugs.
The findings, which could point the way to new approaches for fighting drug-resistant tumours, could have important ramifications for current cancer treatments. Such is its variability and unpredictive nature, generic treatments are not as effective as they could be.
Technion-Israel Institute of Technology researchers, Professor Yehuda Assaraf, discovered that in one mechanism during chemotherapy, a mutation (change in the genetic material) takes place in the protein ABCG2.
This mutation gives ABCG2 the ability to transport a wide variety of anticancer drugs from the anti-folate family outside of the malignant cell. As a result, these malignant cells escape the effects of the drugs and become extremely resistant to anticancer drugs, leading to a rapid spread of the disease.
Anti-folates are used in treating various cancerous growths such as breast cancer, colon cancer, leukaemia, and cancer of the membrane that envelops the lung.
During the study, published in one of two articles in the scientific journal Cancer Research, the researchers succeeded in delaying the mutation from occurring. This enabled the anti-cancer drugs to effectively do their intended work.
"The mutation is an event in which a single amino acid changes in the structure of the ABCG2 protein, which then acts as a pump to transfer out the various anticancer drugs," said Assaraf.
"Acting as 'super-pumps,' the mutated ABCG2 proteins make cancer cells 6,000 times more resistant to various anticancer drugs."
In the second project, Assaraf and doctoral student Ilan Ifergan discovered another resistance mechanism connected to the ABCG2 carrier. They found that cancer cells create disposal areas into which anti-cancer drugs are deposited.
The research revealed that cells neighbouring breast cancers create among themselves balloon-like vesicles that serve as self-emptying units into which the mutated ABCG2 proteins move the anti-cancer drugs.
"The mutated ABCG2 protein is found in large quantities in the extra cellular membrane of these vesicles located among the neighbouring cancer cells," said Assaraf.
"It 'cleans' the cancer cells of chemotherapy drugs such as mitoxantrone and collects them in these vesicles, which enlarge and inflate until the drug concentration is a thousand times greater than in the surrounding cell culture," he added.
The study added that this type of research represented a new resistance mechanism practiced by breast cancer cells to fight the lethal activities of anticancer drugs.
In undertaking this study, the researchers were able to demonstrate that delaying the mutation left the anticancer drugs inside the malignant cells, made it possible to effectively kill the cancer cells located there.
