The HSP90 Inhibitor XL888 Overcomes BRAF Inhibitor Resistance Mediated through Diverse Mechanisms

Abstract

Purpose The clinical use of BRAF inhibitors is being hampered by the acquisition of drug resistance. This study demonstrates the potential therapeutic utility of the HSP90 inhibitor (XL888) in 6 different models of vemurafenib resistance. Experimental design The ability of XL888 to inhibit growth and to induce apoptosis and tumor regression of vemurafenib-resistant melanoma cell lines was demonstrated in vitro and in vivo. A novel mass spectrometry-based pharmacodynamic assay was developed to measure intratumoral HSP70 levels following HSP90 inhibition in melanoma cell lines, xenografts and melanoma biopsies. Mechanistic studies were performed to determine the mechanism of XL888-induced apoptosis. Results XL888 potently inhibited cell growth, induced apoptosis and prevented the growth of vemurafenib resistant melanoma cell lines in 3D cell culture, long-term colony formation assays and human melanoma mouse xenografts. The reversal of the resistance phenotype was associated with the degradation of PDGFRβ, COT, IGFR1, CRAF, ARAF, S6, cyclin D1 and AKT, which in turn led to the nuclear accumulation of FOXO3a, an increase in BIM expression and the downregulation of Mcl-1. In most resistance models, XL888 treatment increased BIM expression, decreased Mcl-1 expression, and induced apoptosis more effectively than dual MEK/PI3K inhibition. Conclusions HSP90 inhibition may be a highly effective strategy at managing the diverse array of resistance mechanisms being reported to BRAF inhibitors and appears to be more effective at restoring BIM expression and downregulating Mcl-1 expression than combined MEK/PI3K inhibitor therapy.

Overcoming Acquired BRAF Inhibitor Resistance in Melanoma via Targeted Inhibition of Hsp90 with Ganetespib

“…Similar activity has been reported for another Hsp90 inhibitor XL888 (32). Unlike the case for a number of mutant kinase-driven malignancies treated with small-molecule inhibitors, to date there is no evidence of secondary "gate-keeper" type mutations in BRAF that account for a resistant phenotype (8).…”

Hsp90 inhibitor as a sensitizer of cancer cells to different therapies (Review)

“…The Hsp90 inhibitor XL888 increased Bcl-2 interacting mediator of cell death expression, decreased Mcl-1 expression, and induced apoptosis more effectively than dual mitogen-activated protein-extracellular signal-regulated in most resistant melanoma models. The reversal of the resistance phenotype was associated with the degradation of PDGFRβ, COT, IGFR1, CRAF, ARAF, S6, cyclin D1 and Akt (139). Inhibition of Hsp90 by GA sensitized melanoma cells also to thermosensitive ferromagnetic particle-mediated by hyperthermia with temperature 43˚C (140).…”

Resveratrol enhanced FOXO3 phosphorylation via synergetic activation of SIRT1 and PI3K/Akt signaling to improve the effects of exercise in elderly rat hearts

“…There is a report that mitochondrial damage will trigger mitophagy in cardiomyocytes through HSP90 and CDC37 activation, but oxidative stress inhibits HSP90 activation and causes cell death with FOXO3 accumulation in the nuclei. FOXO3 is a transcription factor with a function in Fas/FADD signaling pathway protein production and cell death (Joo et al 2011;Paraiso et al 2012;Hsu and Chung 2012).…”