HSP90 inhibitors: multi-targeted antitumor effects and novel combinatorial therapeutic approaches in cancer therapy.
With the rapid rise of tumor resistance, combinatorial anticancer therapies have gained favor over single-molecule inhibition to maximize the suppression of oncogenic pathways. In this regard, HSP90 inhibitors have rapidly emerged as a class of promising drugs that can target multiple oncogenic pathways simultaneously. HSP90 is a highly conserved protein chaperone involved in essential cellular functions such as protein folding and cell signaling in both stressed and unstressed cells. In the last decade, a large number of oncogenic client proteins have been identified to associate with HSP90 and contribute to malignant transformation. Development of HSP90 inhibitors, derived from the natural compound geldanamycin that mimics the ATP binding site of HSP90, was designed to target HSP90 and allow degradation of these client proteins. Preclinical and clinical data with HSP90 inhibitors in various cancer models are promising, and evidences also hint at the potential for tumor-selective cytotoxicity as well as enhanced sensitization to chemo- and radiotherapy. This review will discuss the effects of HSP90 inhibition in cancer, the known mechanistic basis for the oncogenic toxicity and selectivity, as well as the current progress on single or combinatorial therapies with HSP90 inhibitors.
Hwang
Misun
M
Department of Radiation Oncology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232-5671, USA.
Moretti
Luigi
L
Lu
Bo
B
D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000633:toxicity; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use* / Q000633:toxicity; D017209:Apoptosis; D016227:Benzoquinones / Q000737:chemistry / Q000633:toxicity; D003131:Combined Modality Therapy; D004359:Drug Therapy, Combination; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047029:Lactams, Macrocyclic / Q000737:chemistry / Q000633:toxicity; D009369:Neoplasms / Q000188:drug therapy / Q000532:radiotherapy; D017510:Protein Folding; D015398:Signal Transduction
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D016227:Benzoquinones; D018841:HSP90 Heat-Shock Proteins; D047029:Lactams, Macrocyclic; C001277:geldanamycin