Gene expression profiling of human colon cancer cells following inhibitionof signal transduction by 17-allylamino-17-demethoxygeldanamycin, an inhibitor of hsp90 molecular chaperone

A number of molecular therapeutic agents, derived from exploiting our knowl edge of the oncogenic pathways that are frequently deregulated in cancer, a re now entering clinical trials. One of these is the novel agent 17-allylam ino-17-demethoxygeldanamycin that acts to inhibit the hsp90 molecular chape rone. Treatment of four human colon cancer cell lines with iso-effective co ncentrations of this agent resulted in depletion of c-raf-1 and akt and inh ibition of signal transduction. We have used gene expression array analysis to identify genes responsive to treatment with this drug. The expression o f hsp90 client protein genes was not affected, but hsc hsp70, hsp90 beta, k eratin 8, keratin 18 and caveolin-1 were deregulated following treatment. T hese observations were consistent with inhibition of signal transduction an d suggested a possible mechanism of resistance or recovery from 17-allylami no-17-demethoxygeldanamycin treatment. The results shed light on the molecu lar mode of action of the hsp90 inhibitors, and suggest possible molecular markers of drug action for use in hypothesis testing clinical trials.