Melanoma cells are able to build up tolerance to chemotherapy by means of a genetic pathway that inhibits their detection of DNA damage, researchers have learned. Targeting this pathway represents a new treatment approach for fighting this deadly skin cancer.

Dermatologist and biological chemistry assistant professor Anand K. Ganesan, MD, PhD, of the University of California–Irvine (UCI), and colleagues found that the RhoJ and Pak1 genes are key modulators of melanoma cell sensitivity to DNA damage. When chemotherapy induces DNA damage in a melanoma cell, RhoJ activates Pak1, which in turn initiates a molecular cascade that suppresses the cell’s ability to sense this damage. This blunted response to DNA damage blocks the apoptosis (programmed cell death) process, and melanoma cells are allowed 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,” explained Ganesan in a statement issued by UCI to announce the study findings, which appear in Cancer Research.        

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Ganesan’s group has begun to explore methods of inhibiting the genes responsible for the DNA damage tolerance. “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,” he noted.