Cancer cell resistance to chemotherapy drugs - mechanism discovered

Technion-Israel Institute of Technology researchers have discovered new mechanisms developed by cancer cells to become resistant to various chemotherapy drugs.

The findings, which could point the way to new approaches for fighting drug-resistant tumors, were published in two articles in the scientific journal Cancer Research. The projects were carried out in the Technion-Israel Institute of Technology Faculty of Biology under the direction of Professor Yehuda Assaraf.

In the first project, published in mid-September, Assaraf and research student Assaf Shafran discovered that 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. (Anti-folates are used in treating various cancerous growths such as breast cancer, colon cancer, leukemia, and cancer of the membrane that envelops the lung.) 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.

During their study, 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," explains Assaraf. "Acting as 'super-pumps,' the mutated ABCG2 proteins make cancer cells 6,000 times more resistant to various anticancer drugs."

This discovery could have important ramifications for cancer treatments. The researchers are already working on developing drugs to stop the ABCG2 mutation from occurring.

In the second project, published in Cancer Research on December 1, 2005, Assaraf and doctoral student Ilan Ifergan discovered another resistance mechanism connected to the ABCG2 carrier. They found that cancer cells create "waste baskets" into which anti-cancer drugs are deposited.

The pair found that cells neighboring breast cancers create among themselves balloon-like vesicles that serve as self-emptying wastebaskets 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 neighboring cancer cells. 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," explains Assaraf. "This is a completely new resistance mechanism practiced by breast cancer cells to fight the lethal activities of anticancer drugs."

Just as in their earlier study, the researchers were able to demonstrate that delaying the mutation left the anticancer drugs inside the malignant cells, making it possible to very effectively kill the cancer cells located there.