Researchers have used a genome-wide screen to uncover genes that protect lung-cancer cells from Taxol (paclitaxel), a commonly used chemotherapy agent. Without the protection of certain genes, the cancer cells could be killed by drug doses 10,000 times lower than normal. The results could lead to synergistic drug combinations that combat tumors at lower doses with fewer side effects.
The study, performed by researchers at the University of Texas Southwestern Medical Center, is one of the first to use the gene-silencing technique called RNA interference to study drug sensitivity across the entire genome. Led by cell biologist Michael White, the researchers used a library of silencing RNAs to block expression of every known gene in the human genome–there are about 21,000–in only six weeks.
The University of Texas researchers found 87 genes that seemed to regulate the cancer’s sensitivity to the chemotherapy drug. Drugs and natural products that interfere with some of these genes already exist, says White, and researchers can now test whether combining these drugs with Taxol leads to a better response.
The results point to “a way to be more savvy about how to combine drugs,” says Tito Fojo, a senior investigator at the National Cancer Institute’s Center for Cancer Research, although he cautions that “some trial and error” will still be required.
Cancer patients’ responses to chemotherapy agents such as Taxol vary widely and unpredictably. Some patients do not get better; some do but later relapse as their tumors grow resistant to the drug. “We want to identify the molecular basis of the capacity of cancer cells to respond to a drug,” says White. Taxol is given to most lung-cancer patients and is also a common treatment for breast and ovarian cancers. Like all chemotherapy, it causes side effects including pain, nausea, and tingling. A combination treatment that would allow the drug to be given at a much lower dose could make chemotherapy easier on patients.
To identify the target genes, the researchers used an RNA-interference library made commercially available only in the past year and a half. The library allows scientists to reliably silence every human gene.
That broad sweep pointed toward a role for some surprising genes in protecting the cancer cells from Taxol. The drug works by interfering with cell division, but many of the genes uncovered in the Texas screen, such as a sperm-specific protein often found in ovarian-cancer cells, are not implicated in that process.
While the Texas study uncovered some genes that seem to make cancer cells more vulnerable to Taxol than normal cells are, Fojo cautions that new therapies won’t be on the way unless there are good drugs to take advantage of these vulnerabilities. “The more we understand about how drugs work, the better,” he says. “We’re going to see a lot of use of [RNA interference] in this matter.”
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