An update on the status of HSP90 inhibitors in cancer clinical trials.

Abstract

The evolutionary conserved molecular chaperone HSP90 plays an indispensable role in tumorigenesis by stabilizing client oncoproteins. Although, the functionality of HSP90 is tightly regulated, cancer cells exhibit a unique dependence on this chaperone, leading to its overexpression, which has been associated with poor prognosis in certain malignancies. While various strategies targeting heat shock proteins involved in carcinogenesis have been explored, only inhibition of HSP90 has consistently and effectively resulted in proteasomal degradation of its client proteins. To date, a total of 22 HSP90 inhibitors have been tested in 186 cancer clinical trials, as reported by clinicaltrials.gov. Among these trials, 60% have been completed, 10% are currently active, while 30% have been suspended, terminated, or withdrawn. HSP90 inhibitors have been used as single agents or in combination with other drugs for the treatment of various cancer types in clinical trials. Notably, improved clinical outcomes have been observed when HSP90 inhibitors are used in combination therapies, as they exhibit a synergistic antitumor effect. However, as single agents, HSP90 inhibitors have shown limited clinical activity due to drug related toxicity or therapy resistance. Recently, active trials conducted in Japan evaluating TAS-116 (pimitespib) have demonstrated promising results with low toxicity as monotherapy and in combination with the immune check point inhibitor nivolumab. Exploratory biomarker analyses performed in various trials have demonstrated target engagement that suggests potential for identifying patient populations that may respond favorably to the therapy. In this review, we discuss the advances made in the past five years regarding HSP90 inhibitors and their implications in anti-cancer therapeutics. Our focus lies in evaluating drug efficacy, prognosis forecast, pharmacodynamic biomarkers, and clinical outcomes reported in published trials. Through this comprehensive review, we aim to shed light on the progress and potential of HSP90 inhibitors as promising therapeutic agents in cancer treatment.