CHAPTER 4: Exploiting the Dependency of Cancer Cells on Molecular Chaperones
Published:23 Oct 2013
S. Sharp, J. Howes, and P. Workman, in Inhibitors of Molecular Chaperones as Therapeutic Agents, ed. T. D. Machajewski and Z. Gao, The Royal Society of Chemistry, 2013, pp. 126-157.
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More widespread acceptance of molecular chaperones as fertile ground for drug discovery came about relatively recently. The original discovery that Hsp90 is a promising molecular target in oncology was made in 1994 with the observation that the natural product geldanamycin reversed transformation by oncogenic v-SRC via binding to Hsp90 and disrupting the stabilizing complex. We now know that Hsp90 inhibitors exert their anticancer effects by destabilizing and depleting many oncogenic client proteins, including amplified and mutated kinases, notably ERBB2, BRAF, EGFR and ALK, and transcription factors, particularly the androgen and estrogen receptor. Recognition that this combinatorial action is highly tumor-selective and could bring significant therapeutic advantages – especially in circumventing drug resistance – helped greatly to overcome initial concerns of unacceptable toxicity. The trail-blazing geldanamycin analogues cleared the pathway to clinical proof-of-concept and showed that significant therapeutic activity could be obtained at well-tolerated doses in cancers where the major driver oncoprotein is also highly dependent on Hsp90, particularly ERBB2 in breast cancer and mutant EGFR and rearranged ALK in non-small-cell lung cancer. More than 20 Hsp90 inhibitors have now entered the clinic, with some progressing to pivotal studies. There is also considerable interest in other chaperone targets and disease indications.