Hsp90 in Oncology

Over 100 client proteins are thought to depend, to varying degrees, on Hsp90's chaperoning effect for survival. Hsp90 is an important drug target for anticancer agents because many of these client proteins are in pathways disrupted in cancer. Hsp90 is specifically activated in tumor cells where it controls multiple oncogenic proteins (e.g., Her2, Raf), and their downstream signaling molecules (e.g., Akt, Erk) that are critical to the proliferation and survival of tumors. Hsp90 stabilizes mutated proteins (e.g. v-Src) as well as fusion proteins resulting from chromosomal translocations (e.g., Bcr-Abl). Inhibition of Hsp90 leads to degradation of the client proteins, loss of signaling, and inhibition of cell growth. 

Current first generation Hsp90-directed drugs inhibit the growth of a wide range of cancer cells in both solid tumors and blood-based cancers. Recent clinical data have validated this approach to cancer therapy in several tumors including lung, colon, kidney, GIST, pancreatic, breast, prostate, multiple myeloma, leukemia, lymphoma, liver and thyroid. Hsp90 inhibition has also been used as an approach with cancer vaccines. Specifically, the natural product, geldanamycin has been shown to enhance the efficacy of DNA vaccination against Hsp90 client proteins Neu and Met (Lin Mol Ther 2007). Hsp90 is directly and indirectly responsible for the proper function of over 100 proteins including many oncogenes such as Her2, Raf, and Bcr-Abl (Figure 1).

The role of Hsp90 in Chaperoning Client Proteins

Figure 1.

However, when Hsp90 is inhibited, client proteins are unable to retain their correct conformational folding and degrade leading to growth inhibition and cell death (Figure 2).

Figure 2.

A current list of client and co-chaperone interactions can be found at:

http://www.picard.ch/downloads/Hsp90interactors.pdf

Current Hsp90 Inhibitors