Why is this effective HSP90 inhibitor not being developed in HER2+ breast cancer?

Abstract

Inhibition of the HSP90 chaperone leads to degradation of the HER2 receptor. The HSP90 inhibitor tanespimycin in combination with trastuzumab is active in patients with HER2-overexpressing metastatic breast cancer. This combination is one of several HER2-targeted therapies that will significantly improve the outcome of patients with this subtype of breast cancer.

Figure 1

Ansamycins (17-AAG) bind the ADP/ATP switch site in HSP90. HSP90 (in orange) is a molecular chaperone involved in the maturation and refolding of several oncoproteins. It has three domains: an amino terminal region that binds ATP (blue box) and drugs and interacts with co-chaperones (i.e., HSP70, Hip, etc.); a middle domain with docking sites for client proteins and co-chaperones, which participates in generating the ATPase activity; and a carboxy-terminal domain that contains a dimerization motif, a second drug-binding region, and interaction sites for other co-chaperones (i.e. p23, IP). Binding of ATP to the amino-terminal domain and its subsequent hydrolysis by HSP90 result in a conformation that is essential for chaperone activity. All HSP90 inhibitors in clinical development interact with the amino-terminal ATP-binding pocket, prevent ATP binding, and disrupt the chaperone cycle, resulting in ubiquitination and degradation of client proteins such as HER2, EGFR, nuclear steroid receptors, RAF-1, CDK4, AKT, MET, HIF-1α, etc.