Fighting Melanoma's Resistance To Chemotherapy

Blocking the action of a particular protein in our skin could improve the treatment of skin cancers, according to a study published in Oncogene by Philippe Roux, a researcher at the University of Montreal's Institute for Research in Immunology and Cancer (IRIC). "Our findings reveal part of the mechanisms responsible for the resistance of melanoma to anti-cancer treatments, and suggest that a particular protein in our bodies called RSK may be targeted in combination therapies to overcome drug resistance," Roux explained.

Although melanoma accounts for only 4% of all skin cancers, it is responsible for 80% of skin cancer-related deaths worldwide as it is highly invasive and resistant to conventional chemotherapies. Melanoma originates from pigment-producing cells, called melanocytes, located in the skin. The incidence of malignant melanoma is growing rapidly worldwide and there is still no effective therapy to treat it. Approximately 160,000 new cases of the disease are diagnosed each year.

Roux and his team focused their research on a signaling pathway called Ras/MAPK, which is often deregulated in melanoma, but also in lung, colon and pancreatic cancers. A signaling pathway is a chemical chain reaction that causes the cells in our bodies to act in a certain way. In this study, Roux and his team found that a protein in the Ras/MAPK pathway, RSK, contributes to chemoresistance by altering the response of cancer cells to chemotherapeutic agents.

This is the second Oncogene publication for Philippe Roux this year. In a paper published in July, Roux and his colleagues, IRIC Principal Investigators Katherine Borden and Sylvain Meloche, demonstrated that the same protein involved in chemoresistance contributes to melanoma growth, making the protein RSK a promising therapeutic target for treating the disease.

Fighting Melanoma's Resistance To Chemotherapy

Blocking the action of a particular protein in our skin could improve the treatment of skin cancers, according to a study published in Oncogene by Philippe Roux, a researcher at the University of Montreal's Institute for Research in Immunology and Cancer (IRIC). "Our findings reveal part of the mechanisms responsible for the resistance of melanoma to anti-cancer treatments, and suggest that a particular protein in our bodies called RSK may be targeted in combination therapies to overcome drug resistance," Roux explained.

Although melanoma accounts for only 4% of all skin cancers, it is responsible for 80% of skin cancer-related deaths worldwide as it is highly invasive and resistant to conventional chemotherapies. Melanoma originates from pigment-producing cells, called melanocytes, located in the skin. The incidence of malignant melanoma is growing rapidly worldwide and there is still no effective therapy to treat it. Approximately 160,000 new cases of the disease are diagnosed each year.

Roux and his team focused their research on a signaling pathway called Ras/MAPK, which is often deregulated in melanoma, but also in lung, colon and pancreatic cancers. A signaling pathway is a chemical chain reaction that causes the cells in our bodies to act in a certain way. In this study, Roux and his team found that a protein in the Ras/MAPK pathway, RSK, contributes to chemoresistance by altering the response of cancer cells to chemotherapeutic agents.

This is the second Oncogene publication for Philippe Roux this year. In a paper published in July, Roux and his colleagues, IRIC Principal Investigators Katherine Borden and Sylvain Meloche, demonstrated that the same protein involved in chemoresistance contributes to melanoma growth, making the protein RSK a promising therapeutic target for treating the disease.

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Researchers Find Cause Of Chemotherapy Resistance In Melanoma

Researchers with UC Irvine's Chao Family Comprehensive Cancer Center have identified a major reason why melanoma is largely resistant to chemotherapy.

UCI dermatologist Dr. Anand Ganesan and colleagues found a genetic pathway in melanoma cells that inhibits the cellular mechanism for detecting DNA damage wrought by chemotherapy, thereby building up tolerance to cancer-killing drugs.

Targeting this pathway, comprising the genes RhoJ and Pak1, heralds a new approach to treating the deadly skin cancer, which claims nearly 10,000 U.S. lives each year. Study results appear online in Cancer Research, a journal of the American Association for Cancer Research.

"If we can find a way to turn off the pathway responsible for this resistance, melanoma tumors would suddenly become sensitive to therapies we've been using for the last 20 years," said Ganesan, assistant professor of dermatology and biological chemistry at UCI.

In pursuit of a cause for the chemo tolerance, he and his colleagues performed a genome-wide scan for genes controlling drug resistance in melanoma cells. Their search identified RhoJ, a gene normally involved in blood vessel growth. They saw that in response to drug-induced DNA damage in a melanoma cell, RhoJ activated another gene, Pak1, which initiated a molecular cascade suppressing the cell's ability to sense this damage - and blocking the apoptosis process.

"Normally, such drug-induced DNA damage would result in cell death," Ganesan said. "But this blunting of DNA damage response allows melanoma cells to mutate and proliferate. Being capable of rapid adaptation and change is a hallmark feature of this challenging form of cancer and makes it very difficult to treat."

On the heels of this discovery, he and colleagues have begun exploring methods to inhibit the genes responsible for this DNA damage tolerance. What they come up with could one day supplement chemotherapy treatments for melanoma, Ganesan added.

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