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Targeting HER3 by interfering with its Sec61-mediated cotranslational insertion into the endoplasmic reticulum
A Ruiz-Saenz1, M Sandhu1, Y Carrasco2
1Department of Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Oncogene
|January 27, 2015
Summary
A novel small molecule, cotransin CT8, targets HER3 (human epidermal growth factor receptor 3) by blocking its protein production. This approach degrades HER3, enhancing cancer therapy effectiveness.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Human epidermal growth factor receptor 3 (HER3) is implicated in various cancers.
- Targeting HER3 is challenging due to its allosteric kinase domain, rendering traditional inhibitors ineffective.
Purpose of the Study:
- To introduce a novel strategy for eliminating HER3 expression.
- To investigate the efficacy of cotransin CT8 in targeting HER3.
Main Methods:
- Utilized cotransin CT8, a small molecule that binds the Sec61 translocon.
- Prevented cotranslational translocation of nascent HER3 protein, leading to its degradation.
Main Results:
- CT8 selectively degrades HER3 without affecting other HER proteins.
- CT8 treatment suppressed HER3 induction during lapatinib therapy in HER2-amplified cancers.
- CT8 synergistically enhanced lapatinib's apoptotic effects.
Conclusions:
- Targeting Sec61-dependent protein processing offers a novel strategy to eliminate HER3 function.
- Cotransin CT8 represents a promising therapeutic approach for HER3-driven cancers.
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