Abstract
N-terminal HSP90 inhibitors in development have had issues arising from heat shock response (HSR) induction and off-target effects. We sought to investigate the capacity of NCT-58, a rationally-synthesized C-terminal HSP90 inhibitor, to kill trastuzumab-resistant HER2-positive breast cancer stem-like cells. NCT-58 does not induce the HSR due to its targeting of the C-terminal region and elicits anti-tumor activity via the simultaneous downregulation of HER family members as well as inhibition of Akt phosphorylation. NCT-58 kills the rapidly proliferating bulk tumor cells as well as the breast cancer stem-like population, coinciding with significant reductions in stem/progenitor markers and pluripotent transcription factors. NCT-58 treatment suppressed growth and angiogenesis in a trastuzumab-resistant xenograft model, concomitant with downregulation of ICD-HER2 and HSF-1/HSP70/HSP90. These findings warrant further investigation of NCT-58 to address trastuzumab resistance in heterogeneous HER2-positive cancers.
Highlights
Heat shock protein 90 (HSP90) is a chaperone that governs the maturation, stabilization, and activation of client proteins [1, 2]
HSP90 interacts with a variety of pathways that can become oncogenic, and its aberrant activity is implicated in tumorigenesis and cancer progression [2,3,4]
NCT-58-dependent apoptosis is mediated by caspase activation in human epidermal growth factor receptor 2 (HER2)-positive breast cancer cells We first sought to evaluate the effect of NCT-58 on cell viability and apoptosis in HER2-positive breast cancer cells
Summary
Heat shock protein 90 (HSP90) is a chaperone that governs the maturation, stabilization, and activation of client proteins [1, 2]. Key mechanisms responsible for trastuzumab resistance include HER2/HER3 and HER2/EGFR interactions, hyperactivation of PI3K/Akt signaling, and accumulation of truncated forms of HER2 [10, 11]. Truncated p95HER2 is a constitutively active form of the tyrosine kinase that activates downstream signaling through dimerization with other HER family members [11,12,13]. These trastuzumab resistance-related factors are HSP90 client proteins [5,6,7, 14], and the inhibition of HSP90 may suppress several potent oncogenic drivers and trastuzumab-refractory factors
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