Researchers with UC Irvineâ€™s ChaoÂ Family Comprehensive Cancer Center have identified a major reason why melanomaÂ is largely resistant to chemotherapy.
UCI dermatologist Dr. Anand GanesanÂ and colleagues found a genetic pathway in melanoma cells that inhibits theÂ cellular mechanism for detecting DNA damage wrought by chemotherapy, therebyÂ building up tolerance to cancer-killing drugs.
Targeting this pathway, comprisingÂ the genes RhoJ and Pak1, heralds a new approach to treating the deadly skinÂ cancer, which claims nearly 10,000 U.S. lives each year. Study results appearÂ online in Cancer Research, a journal of the American Association for CancerÂ Research.
â€śIf we can find a way to turn offÂ the pathway responsible for this resistance, melanoma tumors would suddenlyÂ become sensitive to therapies weâ€™ve been using for the last 20 years,â€ť saidÂ Ganesan, assistant professor of dermatology and biological chemistry at UCI.
In pursuit of a cause for the chemoÂ tolerance, he and his colleagues performed a genome-wide scan for genes controllingÂ drug resistance in melanoma cells. Their search identified RhoJ, a geneÂ normally involved in blood vessel growth. They saw that in response to drug-inducedÂ DNA damage in a melanoma cell, RhoJ activated another gene, Pak1, which initiatedÂ a molecular cascade suppressing the cellâ€™s ability to sense this damage â€” andÂ blocking the apoptosis process.
â€śNormally, such drug-induced DNAÂ damage would result in cell death,â€ť Ganesan said. â€śBut this blunting of DNA damageÂ response allows melanoma cells to mutate and proliferate. Being capable of rapid adaptation and change is a hallmark feature of this challenging form ofÂ cancer and makes it very difficult to treat.â€ť
On the heels ofÂ this discovery, he and colleagues have begun exploring methods to inhibit theÂ genes responsible for this DNA damage tolerance. What they come up with could oneÂ day supplement chemotherapy treatments for melanoma, Ganesan added.
Hsiang Ho,Â Jayavani Aruri, Rubina Kapadia and Hootan Mehr of UCI and Michael A. White ofÂ the University of Texas Southwestern Medical Center at Dallas participated inÂ the study, which received support from the National Institutes of Health, the UniversityÂ of California Cancer Research Coordinating Committee, the American CancerÂ Society, Outrun the Sun Inc. and the Robert A. Welch Foundation.
About the University of California, Irvine:Â Founded in 1965, UCI is a top-ranked university dedicated to research, scholarshipÂ and community service. Led by Chancellor Michael Drake since 2005, UCI is amongÂ the most dynamic campuses in the University of California system, with nearly 28,000Â undergraduate and graduate students, 1,100 faculty and 9,000 staff. OrangeÂ Countyâ€™s second-largest employer, UCI contributes an annual economic impact ofÂ $4 billion. For more UCI news, visit www.today.uci.edu.
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