A novel HSP90 inhibitor SL-145 suppresses metastatic triple-negative breast cancer without triggering the heat shock response

Abstract

Despite recent advances, there remains a significant unmet need for the development of new targeted therapies for triple-negative breast cancer (TNBC). Although the heat shock protein HSP90 is a promising target, previous inhibitors have had issues during development including undesirable induction of the heat shock response (HSR) and off-target effects leading to toxicity. SL-145 is a novel, rationally-designed C-terminal HSP90 inhibitor that induces apoptosis in TNBC cells via the suppression of oncogenic AKT, MEK/ERK, and JAK2/STAT3 signaling and does not trigger the HSR, in contrast to other inhibitors. In an orthotopic allograft model incorporating breast cancer stem cell-enriched TNBC tumors, SL-145 potently suppressed tumor growth, angiogenesis, and metastases concomitant with dysregulation of the JAK2/STAT3 signaling pathway. Our findings highlight the potential of SL-145 in suppressing metastatic TNBC independent of the HSR.

Recent advances in therapeutic strategies for triple-negative breast cancer

“…Onalespib plus paclitaxel is currently being studied for the treatment of TNBC patients in a phase Ib trial (NCT02474173). In addition, SL-145, a novel C-terminal inhibitor of HSP90, has demonstrated antitumor and antimetastatic effects on TNBC cells in a preclinical study and may represent a promising agent in the future [ 121 ].…”

Ebastine impairs metastatic spread in triple-negative breast cancer by targeting focal adhesion kinase

“…After a period of 24 h following the final administration of EBA, the animals were anesthetized and subjected to NightOWL LB983 bioluminescence imaging (BLI) (Berthold Technologies, TN). The procedures were performed as previously described [ 36 ].…”

Heat shock protein 90: biological functions, diseases, and therapeutic targets

“…Importantly, SL-145 achieves these effects without triggering the HSR. 245 Zhang et al 246 demonstrated that penisuloxazin A reverses the epithelial-mesenchymal transformation of breast cancer cells and enhances the cytotoxicity of natural killer cells against breast cancer cells. Dai et al 247 showed that penicisulfuranol A inhibits multiple HSP90 client proteins, induces apoptosis and inhibits xenograft tumor growth of HCT116 cells both in vitro and in vivo without inducing HSP70.…”

“…It has demonstrated the ability to induce apoptosis in TNBC cells by effectively suppressing Akt, MEK/ERK, and JAK2/STAT3 signaling pathways. Importantly, SL‐145 achieves these effects without triggering the HSR 245 …”