Fig. 7. Hypothetical model illustrating multiple actions of NCT-58 on cancer stem-like properties, HER2 signaling, and trastuzumab resistance in HER2-positive breast cancer.

i NCT-58 targets the C-terminal domain of HSP90 independent of the HSR and effectively induces apoptosis via the activation of cleaved caspase-3/7. ii NCT-58 downregulates the expression and phosphorylation of HER2, HER3, and EGFR as well as suppresses truncated p95HER2 accumulation and Akt activation, concomitant with downregulation of the Ras/Raf/Mek/Erk signaling pathway. iii NCT-58 kills not only proliferating tumor cells, but also eliminates BCSC-like cells. The latter responses are accompanied by the reduction of stem/progenitor markers CD44/ALDH1 and expression of the pluripotent transcription factors Nanog/Oct4/Sox2 as well as downregulation of HSF-1/HSF70/HSP90. [Heat shock response, HSR; Heat shock factor-1, HSF-1, Heat shock element, HSE].