![]() Materials used (details listed in Supplementary Information) We sought to determine whether targeting the C-terminal domain of HSP90 could lead to effective suppression of oncogenic signaling while avoiding induction of the pro-survival HSR. HSP70 is known to be a pro-survival factor that hinders the induction of apoptosis, leading to drug resistance. In general, HSP90 inhibitors targeting the N-terminus trigger translocation of the transcription factor HSF-1 to the nucleus, leading to further upregulation of HSP70, HSP90, and other HSPs, followed by activation of the survival cascade known as the heat shock response (HSR). Over the last two decades, the development of HSP90 inhibitors has largely focused on targeting the N-terminal ATP-binding domain, however, none have succeeded to date. ![]() Heat shock protein 90 (HSP90) is a molecular chaperone that maintains the structural and functional integrity of numerous client proteins many of which have oncogenic potential, including AKT/MEK/JAK2/STAT3 and pluripotent transcription factors. Although chemo- and radiation therapies are often successful at destroying a large proportion of the tumor bulk, recurrence is thought to occur due to the presence of these subpopulations and their targeting may be essential to elimination of the entire tumor cell population. Evidence suggests that breast cancer stem cells (BCSCs) harboring tumor-initiating potential and self-renewal capacity may be at least partially responsible for such poor clinical outcomes. Despite numerous clinical trials for single and combination therapies of the PI3K/AKT, MEK/ERK, JAK2/STAT3, and mTOR signaling pathways, none have yet resulted in an improvement in overall survival for TNBC patients within an acceptable therapeutic window. Standard treatment for TNBC patients relies on broadly cytotoxic anticancer drugs due to the absence of commercially-available targeted therapies. Triple-negative breast cancer (TNBC) is the most aggressive and lethal subtype of breast cancer with high heterogeneity, associated with increased risks of recurrence and metastasis.
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