Many potentially effective cancer treatments are undone by the onset of resistance to the treatment. In order to circumvent this problem, D. Gary Gilliland and colleagues, of Brigham and Women's Hospital, have developed a strategy using the latest technologies involving small interfering RNA to enhance cancer treatment even in a situation where drug resistance has developed. Small interfering RNAs work by inhibiting the expression of specific genes that have a matching complimentary sequence. The authors theorized that this type of RNA treatment might boost the effectiveness of anti-cancer treatments. They tested their theory in a form of leukemia that is caused when two genes fuse to form an unregulated gene that transforms normal cells into cancer cells, a gene called TEL-PDGFbetaR. This form of leukemia is generally treated with a commonly used anti-cancer drug called imatinib, which is a small molecule protein inhibitor that blocks the activity of the protein produced from the fusion gene TEL-PDGFbetaR. Gilliland and colleagues created a small inhibitory RNA specific to the TEL-PDGFbetaR fusion gene, and found that its expression did indeed exclusively reduce the expression of the oncogenic TEL-PDGFbetaR by 90%. While this alone was not sufficient to kill the cancer cells, this treatment enhanced the ability of imatinib to kill these cancer cells. Further, when they tested this strategy with imatinib-resistant cells, the inhibitory RNA was still able to reduce this gene's expression, and enhanced the activity of another small molecule inhibitor. This study demonstrates that small inhibitory RNA treatment may be an extremely useful adjunct to cancer treatments, and can also aid in overcoming the common problem of drug resistance when used in conjunction with anticancer agents.

TITLE: Stable expression of small interfering RNA sensitizes TEL-PDGFbetaR to inhibition with imatinib or rapamycin

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Contact: Laurie Goodman
press_releases@the-jci.org
212-342-4159
Journal of Clinical Investigation
15-Jun-2004