Related Experiment Video
Updated: Feb 16, 2026
Generation of High-Throughput Three-Dimensional Tumor Spheroids for Drug Screening
Published on: September 5, 2018
Inhibition of HSP90 sensitizes a novel Raf/ERK dual inhibitor CY-9d in triple-negative breast cancer cells
Yujuan Chen1, Xiaoyun Wang1, Chuan Cao2
1State Key Laboratory of Biotherapy and Department of Breast Surgery, West China Hospital, West China Medical School, Sichuan University and Collaborative Innovation Center for Biotherapy, Chengdu 610041, China.
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.
Insights
Triple-negative breast cancer (TNBC) shows resistance to Raf/ERK inhibitors. Combining HSP90 and Raf/ERK inhibitors overcomes this resistance, enhancing apoptosis and suppressing tumor growth with low toxicity.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- The mitogen-activated protein kinase (MAPK) pathway, involving Raf and extracellular signal-regulated kinases (ERK), is crucial in breast cancer apoptosis resistance.
- The Raf/ERK dual inhibitor CY-9d exhibits limited efficacy in triple-negative breast cancer (TNBC) compared to ER/PR-positive cells.
Purpose of the Study:
- To investigate the mechanisms underlying CY-9d resistance in TNBC.
- To identify potential therapeutic strategies to enhance CY-9d efficacy in TNBC.
Main Methods:
- Quantitative proteomic iTRAQ analysis and bioinformatics to identify differentially expressed proteins.
- Western blotting and RNA interference to elucidate protein interactions and signaling pathways.
- In vitro and in vivo studies evaluating drug efficacy, apoptosis induction, and toxicity.
Main Results:
- HSP90 identified as a key mediator in the Raf/ERK pathway in TNBC.
- Downregulated IQGAP1 was found to promote HSP90-mediated bypass signaling, contributing to drug resistance.
- Combination therapy with HSP90 and CY-9d inhibitors demonstrated synergistic therapeutic effects and apoptosis induction in TNBC cells.
- CY-9d suppressed tumor growth and induced mitochondrial apoptosis in vivo with minimal toxicity.
Conclusions:
- HSP90 acts as a bypass mediator in the Raf/MEK/ERK cascade in TNBC, contributing to resistance against Raf/ERK inhibitors.
- Combined inhibition of HSP90 and Raf/ERK pathways presents a promising therapeutic strategy for TNBC.
- This combination therapy enhances tumor growth suppression, downstream pathway blockade, and apoptosis induction in TNBC.
Related Concept Videos
02:34Inhibition of Cdk Activity
02:57Targeted Cancer Therapies
There are several types of targeted therapies against...