Researchers with UC Irvine‚Äôs 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.
‚ÄúIf we can find a way to turn off¬†the pathway responsible for this resistance, melanoma tumors would suddenly¬†become sensitive to therapies we‚Äôve been using for the last 20 years,‚ÄĚ 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‚Äôs ability to sense this damage ‚ÄĒ and¬†blocking the apoptosis process.
‚ÄúNormally, such drug-induced DNA¬†damage would result in cell death,‚ÄĚ Ganesan said. ‚ÄúBut 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.‚ÄĚ
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.
Hsiang Ho,¬†Jayavani Aruri, Rubina Kapadia and Hootan Mehr of UCI and Michael A. White of¬†the University of Texas Southwestern Medical Center at Dallas participated in¬†the study, which received support from the National Institutes of Health, the University¬†of California Cancer Research Coordinating Committee, the American Cancer¬†Society, Outrun the Sun Inc. and the Robert A. Welch Foundation.
About the University of California, Irvine:¬†Founded in 1965, UCI is a top-ranked university dedicated to research, scholarship¬†and community service. Led by Chancellor Michael Drake since 2005, UCI is among¬†the most dynamic campuses in the University of California system, with nearly 28,000¬†undergraduate and graduate students, 1,100 faculty and 9,000 staff. Orange¬†County‚Äôs second-largest employer, UCI contributes an annual economic impact of¬†$4 billion. For more UCI news, visit www.today.uci.edu.
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