Targeting Heat-Shock Protein 90 in Cancer: An Update on Combination Therapy

Abstract

Heat-shock protein 90 (HSP90) is an important molecule chaperone associated with tumorigenesis and malignancy. HSP90 is involved in the folding and maturation of a wide range of oncogenic clients, including diverse kinases, transcription factors and oncogenic fusion proteins. Therefore, it could be argued that HSP90 facilitates the malignant behaviors of cancer cells, such as uncontrolled proliferation, chemo/radiotherapy resistance and immune evasion. The extensive associations between HSP90 and tumorigenesis indicate substantial therapeutic potential, and many HSP90 inhibitors have been developed. However, due to HSP90 inhibitor toxicity and limited efficiency, none have been approved for clinical use as single agents. Recent results suggest that combining HSP90 inhibitors with other anticancer therapies might be a more advisable strategy. This review illustrates the role of HSP90 in cancer biology and discusses the therapeutic value of Hsp90 inhibitors as complements to current anticancer therapies.

Alvespimycin Inhibits Heat Shock Protein 90 and Overcomes Imatinib Resistance in Chronic Myeloid Leukemia Cell Lines

“…HSPs significantly impact tumorigenesis by interfering with several signaling pathways that culminate in cancer cell proliferation, survival, and metastization [ 11 ]. Over the years, multiple HSP inhibitors have been developed for the different HSPs, several designed to target HSP90 [ 8 , 11 ]. The potential of these drugs relies on higher affinity to cancer cells compared to normal cells.…”

“…HSP90 forms a multichaperone complex with HSP70, HSP40, P23, HOP (HSP organizing proteins), and ATP to perform these actions. In cancer cells, the expression of HSP90 is 2 to 10-fold higher than in normal cells, as described for CML cells [ 8 ].…”

“…Multiple oncoproteins have been identified as HSP90 client proteins, such as mutant c-KIT, HER2, mutant EGFR, BRAF, and BCR-ABL [ 8 ]. Targeting HSP90 to inhibit chaperone activity and promote client protein degradation may be an effective strategy in cancer treatment.…”

Dialog beyond the Grave: Necrosis in the Tumor Microenvironment and Its Contribution to Tumor Growth

“…Increased HSPs levels may also cause impaired apoptotic response and promote tumor growth by stabilizing proteins involved in cancer survival [ 164 , 165 ] as well as promote radioresistance [ 166 ] or EMT [ 167 , 168 ]. HSPs are also the key target proteins in novel cancer therapies (recently reviewed in [ 169 ]) since they may promote chemoresistance [ 170 , 171 ]. Moreover, HSP90α converts monocytes to immunosuppressive myeloid cells in melanoma through TLR4 signaling [ 139 ].…”

Investigation of Cellular Response to the HSP90 Inhibition in Human Cells Through Thermal Proteome Profiling

“…The role of HSP90 in cancer has been associated with tumor progression, drug resistance, and metastasis ( 11 , 12 , 13 ). Therefore, inhibiting HSP90 is promising for anti-tumor therapy ( 14 , 15 ).…”