HSP90 inhibitors for cancer therapy and overcoming drug resistance

Abstract

Since the initial discovery of heat shock protein 90 (HSP90) as a target for anticancer therapy, tremendous progress has been made in developing a multitude of potent first- and second-generation HSP90 inhibitors. Promising activity has been reported with 17-AAG in combination with trastuzumab in HER2 positive breast cancer refractory to trastuzumab therapy and more recently in ALK-mutated lung cancers. However, the full potential of this class of agents is yet to be realized. This review not only provides an up-to-date overview of the clinical development of HSP90 inhibitors and their companion biomarker assays but also provides insight into the less-understood role of HSP90 in tumor evolution and drug resistance. A better understanding of these important concepts will facilitate the optimal and expedient development of this class of agents, ultimately fulfilling their promise as potent anticancer therapeutics and leading to the regulatory approval of the first-in-class HSP90 inhibitor.