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Editor's Note: Image of Dr Jean Y. J. Wang, Ph.D. (28K)


drwang_small.jpg (3544 bytes)Drug resistance has long been one of medicine’s most vexing problems. Often cancer cells are initially sensitive to chemotherapy, only to develop resistance after a few treatments. In up to 30 percent of cases, the cancer cells are completely unaffected by chemotherapy drugs from the outset of treatment. The cause for this drug resistance, whether acquired or pre-existing, has eluded scientists.

Now researchers at the University of California, San Diego (UCSD) Cancer Center have discovered a fundamental basis for drug resistance, which they report in the June 24 issue of the journal Nature. The research team, led by Jean Y. J. Wang, Ph.D., Associate Director for Basic Research at UCSD Cancer Center, has discovered a signaling pathway that is activated by the chemotherapy drug cisplatin. Drug resistance occurs when this pathway is defective.

Here is how it works. Chemotherapeutic agents, such as cisplatin, kill cancer cells by damaging the cell’s DNA. When its DNA is damaged, the cell commits suicide rather than duplicating itself with defective DNA. This cell-death process, called apoptosis, is initiated by a tumor suppressor gene called MLH1, which detects the damage through a mechanism called mismatch repair. The mismatch repair protein works to repair minor damage, but when the damage is too great it sends instructions to another gene, called c-Abl, which in turn signals yet another gene, called p73. Together, c-Abl and p73 trigger the suicide.

"In up to 30 percent of cancer cases, the cancer cells have lost the mismatch repair mechanism and, thus, cannot signal c-Abl and p73 to self-destruct in response to cisplatin," said Wang, who is also professor of biology at UCSD. "If you lose mismatch repair, you’re in double jeopardy because your DNA is more easily mutated, which sets the stage for cancer, and you are super-resistant to chemotherapy."

Identification of this cellular pathway opens new doors for scientists to combat drug resistant cancers because it provides a specific target. In cancer cells that have lost the DNA repair protein, Wang and colleagues have found that the other components of the suicide pathway remain. Therefore, it should be possible to activate the latent suicide pathway and kill the drug resistant cancer cells with tools other than the conventional chemotherapy drugs. Research in this area is continuing in Wang's laboratory at UCSD.

Wang’s work has broad application for treating many types of cancer, according to Richard Kolodner, Ph.D., professor of medicine with the UCSD School of Medicine and member of the Ludwig Institute for Cancer Research. Kolodner discovered the MLH1 gene in 1994, and is the leading authority on mismatch repair.

"Defective mismatch repair and the resulting drug resistance represents a huge problem in cancer care," Kolodner said. "The discovery of this suicide pathway is a fundamental finding that may very well change the way cancer is treated in the future."

Co-authors on the paper are JianGen Gong and Hong-Qiong Yang of the Department of Biology and the Cancer Center at UCSD; Antonio Costanzo, Gerry Melino and Massimo Levrero of the University of Rome; and William G. Kaelin Jr. of the Howard Hughes Medical Institute and the Dana Farber Cancer Institute in Boston. This work was supported by a grant from the National Cancer Institute.