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New mechanisms that malignant cells develop to overcome anticancer drugs

Technion researchers discovered that breast cancer cells form a common "vesicle" into which they release the drug

Avi Blizovsky

The Technion researchers were able to discover new resistance mechanisms that cancer cells develop and with the help of which they become particularly stable against various anti-cancer drugs. This is what the prestigious scientific journal Cancer Research reveals in two separate articles published in mid-September and last week, following two studies conducted in the Faculty of Biology at the Technion under the direction of Professor Yehuda Asraf.

In the first study, Professor Asraf and research student Assaf Shafaran discovered that during the chemotherapy treatment, a mutation (change in the hereditary material) that occurs in the 2ABCG protein makes it have an extraordinary ability to throw out of the malignant cell a wide variety of anticancer drugs from the antipolote family. These drugs are used in the treatment of various cancerous tumors such as breast cancer, colon cancer, blood cancer (leukemia) as well as the pleural membrane (which surrounds the lung). As a result, these malignant cells become extremely resistant to the anti-cancer drugs, which leads to a rapid worsening of the cancer and the death of the patient. Later in the study, the researchers were able to effectively inhibit the 2ABCG mutant carrier and thus proved that the malignant cells that have developed drug resistance can be killed very effectively. "The mutation is an event in which a single 'white' (amino acid) was replaced in the structure of the 2ABCG protein, which acts as a pump that expels various anti-cancer drugs. This mutation gives this carrier the incredible ability to make cancer cells more than 6,000 times more resistant to various anti-cancer drugs," explains Professor Asraf. "The mutation turns the 2ABCG protein into a 'super pump' that is particularly effective in throwing anti-cancer drugs out of the malignant cell," he adds.

This discovery may have important therapeutic implications, as researchers have recently been working on the development of particularly effective drugs that disable the activity of dumping anti-cancer drugs by this super pump.

In the second study, published in Cancer Research on December 2, Professor Asraf and PhD student Ilan Ifergan discovered another new resistance mechanism also associated with the 2ABCG carrier. In this study, it was discovered that adjacent breast cancer cells create a kind of vesicle between them that serves as an "emptying garbage can" into which they throw the anti-cancer drugs that are supposed to kill them and thus become resistant. "The XNUMXABCG carrier found in high quantity in the membrane of this extracellular vesicle that is found between adjacent cancer cells, 'cleanses' the contents of cancer cells from anticancer drugs such as mitoxantrone and concentrates them inside the vesicle, which is increasing in volume, up to a drug concentration that is a thousand times higher than outside the malignant cell." Professor Asraf clarifies. "This is a completely new resistance mechanism used by breast cancer cells to overcome the lethal activity of anti-cancer drugs."

As in the previous study, here too the researchers were able to show that inhibiting the pump left the anti-cancer drug inside the malignant cells, thus proving that the resistant cancer cells can be eradicated very effectively when the pumping activity of the drug into the bladder is disabled.

Cancer research expert

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