Drug-Resistant Melanoma Cells Become 'Addicted' to Cancer Drugs and Shrink When Treatment is Interrupted

melanoma
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Melanoma tumors that develop resistance to anti-cancer drug vemurafenib, or more commonly known as Zelboraf, also develop addiction to the drug, a new study revealed.

Scientists involved in the study, published in the journal Nature, were able to successfully exploit the mechanism by which melanoma cells become resistant and "addicted" to the cancer drug with intermittent dosing.

Researchers say the latest findings suggest that employing an on-again, off-again treatment schedule of the cancer drug may be a simple way to help treat skin cancer patients with late-stage, drug-resistant melanoma.

Scientists explain that one mechanism by which harmful melanoma cells become resistant to vemurafenib enables the cancer cells to turn the tables on the anti-cancer medication that's supposed to kill it. Researchers said that mechanism allows melanoma cells to use vemurafenib to boost its own growth, which often results in rapidly progressing, deadly, drug resistant tumors.

However, scientists recently discovered a way to take advantage of the cancer's "addiction" to vemurafenib. They found that adjusting the drug dosage and introducing an 'intermittent dosing' strategy or an on-again, off-again treatment schedule lengthened the life of mice with drug-resistant melanoma tumors.

"Remarkably, intermittent dosing with vemurafenib prolonged the lives of mice with drug-resistant melanoma tumors," co-lead researcher Martin McMahon, PhD, the Efim Guzik Distinguished Professor of Cancer Biology in the UCSF Helen Diller Family Comprehensive Cancer Center, said in a statement.

Researchers said that the latest findings from the mouse study show that it is theoretically possible that a similar approach could also work in people.

Like all cancers, melanoma starts with normal cells in the body that accumulate mutations and undergo transformations that cause them to grow and metastasize. One of the most common mutations in melanoma occurs in a gene called BRAF. Researchers say that more than half of all patients with melanoma express mutated BRAF.

The U.S. Food and Drug Administration approved Vemurafenib in 2011 for treating patients in late-stage melanoma with BRAF mutations. However, researchers note that the effects of the drug do not last forever. While melanoma tumors may initially shrink, most patients on vemurafenib suffer cancer recurrence in the long run with a lethal, drug-resistant form of melanoma.

Researchers said that the same resistance has been observed in mice. They implanted small melanoma tumor fragments in mice, and found that while the tumors initially shrink in response to the drug, eventually mice will cease to respond to the drug and their tumors will evolve to a resistant form.

A team of researchers from California and Switzerland found that when melanoma cells are exposed to vemurafenib, they become resistant by making more of the BRAF protein - the very target of the drug itself.

They explain that intermittent dosing of vemurafenib works because cancers that have developed resistance to the drug also become addicted to it, therefore when the drug is temporarily removed, the drug-resistant tumors start to shrink.

McMahon and her team found that when they stopped administering the medication to mice with resurgent, resistant tumors, the cancerous tumors shrank once again.

Furthermore, researchers revealed that mice continuously treated with vemurafenib all died of drug-resistant disease within about 100 days, while those treated with vemurafenib but with regular breaks all lived past 100 days.

"Vemurafenib has revolutionized treatment of a specific subset of melanoma expressing mutated BRAF, but its long-term effectiveness is diminished by the development of drug resistance," McMahon concluded. "By seeking to understand the mechanisms of drug resistance, we have also found a way to enhance the durability of the drug response via intermittent dosing."

Melanoma is the most aggressive type of skin cancer. According to the National Cancer Institute, around 76,250 people in the United States were newly diagnosed with it in 2012 alone, and around 9,180 people died from the disease last year.

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