Inhibition of HSP90 sensitizes a novel Raf/ERK dual inhibitor CY-9d in triple-negative breast cancer cells.

Yujuan Chen,Shufang Liang,Cheng Peng,Gu He,Xiaodong Wang,Chuan Cao,Xiaoyun Wang,Leilei Fu

doi:10.18632/oncotarget.22119

Yujuan Chen, Shufang Liang + Show 6 more

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https://doi.org/10.18632/oncotarget.22119

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Abstract

Raf and extracellular signal-regulated kinases (ERK) are both important therapeutic targets in the mitogen-activated protein kinase (MAPK) pathway, and play crucial roles in the apoptosis resistance of breast cancer cells. In the present study, cytotoxic and apoptosis-inducing activities of the Raf/ERK dual inhibitor CY-9d were found to be restricted in triple negative breast cancer (TNBC) cells compared with ER/PR-positive cells. Based on the analysis of differentially expressed proteins using a quantitative proteomic iTRAQ method and bioinformatics analysis, HSP90 was found to identify as a potential mediator between Raf and ERK in TNBC cells. Western blotting and RNA interference suggested that down-regulated IQGAP1 can attenuate the routine Raf/MEK/ERK cascade and recruit HSP90 as a bypass pathway. Simultaneous treatment with the HSP90 inhibitor and CY-9d at sub-therapeutic doses was found to produce synergistic therapeutic and apoptosis-inducing effects in TNBC cells. Moreover, CY-9d was also found to suppress breast cancer growth, inhibit the activation of Raf/ERK, and induce mitochondrial apoptosis in vivo without remarkable toxicity. These results support the combination of HSP90 and Raf/ERK inhibitors as a potential target therapeutic strategy with enhanced tumor growth suppression, downstream pathway blockade, and greater induction of apoptosis.

Highlights

According to cancer statistics published in 2017, breast cancer accounts for approximately 30% of female cancer cases, and after lung cancer, is the second cancerrelated mortality in females worldwide [1]
Cytotoxic and apoptosis-inducing activities of the Raf/extracellular signal-regulated kinases (ERK) dual inhibitor CY-9d were found to be restricted in triple negative breast cancer (TNBC) cells compared with ER/PR-positive cells
The present study investigates to what extent TNBC cells bypass MEK inhibition and resist apoptosis induced by the Raf/ERK dual inhibitor CY-9d, high activation of heat shock protein 90 (HSP90) client proteins, and HSP90 itself

Summary

Introduction

According to cancer statistics published in 2017, breast cancer accounts for approximately 30% of female cancer cases, and after lung cancer, is the second cancerrelated mortality in females worldwide [1]. Numerous studies have suggested that hyper-activation of the MAPK signaling pathway is common in breast cancer, and therapies targeting MAP kinases have played important roles in the treatment of breast cancer [2-11]. In the MAPK signaling pathways, the Raf/MEK/ERK cascade is activated by mutant KRAS and plays a crucial role in the regulation of cancer cell proliferation, differentiation, survival and migration [12-15]. The oncoprotein Ras is one of the main regulators of receptor tyrosine kinase-induced cell proliferation and survival in both normal and cancerous cells. Activated Ras can phosphorylate proteins in the Raf/MEK/ERK, PI3K/ AKT/mTOR and other signaling pathways [16-19]. As a direct downstream substrate of Ras, Raf activation leads to the phosphorylation of MEK, the kinase that activates ERK

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