Heat shock protein 90-Androgen receptor complex (HSP90-AR complex) (HSP90-AR complex)

The Heat shock protein 90-Androgen receptor (HSP90-AR) complex is a multi-protein assembly where the molecular chaperone HSP90 facilitates the proper folding, stabilization, and activation of the androgen receptor (AR) (Pratt & Toft, 2003, Exp Biol Med). In its inactive state, the AR is sequestered in the cytoplasm by HSP90 and other co-chaperones, which maintain the receptor in a conformation ready for high-affinity ligand binding (Solit et al., 2002, Cancer Research). Upon binding to androgens, the AR undergoes a conformational change, dissociates from the HSP90 complex, and translocates to the nucleus to function as a transcription factor. This complex is a significant therapeutic target in oncology, especially for castration-resistant prostate cancer (CRPC), where AR signaling remains a primary driver of disease progression despite low androgen levels (Ferraldeschi et al., 2014, Cancer Res). Pharmacological inhibition of HSP90 disrupts this complex, triggering the misfolding and subsequent proteasomal degradation of the AR, including its oncogenic splice variants like AR-V7 (Scher et al., 2011, J Clin Oncol). Consequently, targeting the HSP90-AR complex offers a strategy to overcome resistance to traditional androgen deprivation therapies and direct AR antagonists. However, the clinical development of drugs targeting this complex has faced challenges due to off-target toxicities, such as hepatotoxicity and ocular disturbances (Neckers & Workman, 2012, Clin Cancer Res).

Other names

HSP90-AR heterocomplexAR-HSP90 complexHeat shock protein 90-Androgen receptor chaperone complexHSP90-AR interaction

HSP90 inhibition leading to proteasomal degradation of the androgen receptor and disruption of the chaperone-client interaction.