HER2-mTOR signaling-driven breast cancer cells require ER-associated degradation to survive
Navneet Singh1, Rashika Joshi1, Kakajan Komurov2
1Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Abstract:
Targeting non-oncogenic vulnerabilities may provide additional therapeutic approaches in tumors that are resistant to oncogene-targeted therapy. Using a computational pathway-based approach, we interrogated clinical breast cancer genomic data sets for candidate non-oncogenic vulnerabilities in breast cancers that have genomic amplification of ERBB2, which encodes human epidermal growth factor 2 (HER2). HER2-positive (HER2(+)) breast cancers showed increased expression of genes encoding proteins in the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway. Genetic ablation or pharmacological inhibition of ERAD led to irrecoverable ER stress and selectively killed HER2(+) breast cancer cells. Cell death caused by ERAD inhibition partially depended on increased HER2-mTOR signaling, which imposed an increased proteotoxic burden on the ER. Cell death in response to ER stress required the IRE1α-JNK pathway, which was selectively suppressed in HER2(+) breast cancers by phosphatases that inactivate JNK. Accordingly, the cytotoxicity of inhibiting ERAD as well as JNK phosphatases was synergistic in HER2(+) but not in HER2-negative breast cancer cells. Therefore, our study suggests that reactivation of oncogene-induced stress by targeting stress-adaptive pathways may be a beneficial approach for therapy-resistant breast cancers.
Insights
Targeting the ERAD pathway selectively kills HER2-positive breast cancer cells by inducing lethal ER stress. Combining ERAD inhibition with JNK phosphatase blockade offers a synergistic approach for therapy-resistant HER2(+) breast cancers.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Targeting non-oncogenic vulnerabilities is crucial for overcoming resistance to oncogene-targeted therapies in cancer.
- Genomic amplification of ERBB2 (HER2) defines a subset of breast cancers with distinct therapeutic challenges.
Purpose of the Study:
- To identify non-oncogenic vulnerabilities in HER2-amplified breast cancers.
- To investigate the role of the endoplasmic reticulum-associated degradation (ERAD) pathway in HER2(+) breast cancer.
- To explore therapeutic strategies targeting ERAD and associated stress pathways.
Main Methods:
- Computational pathway-based analysis of clinical breast cancer genomic data.
- Genetic and pharmacological inhibition of the ERAD pathway in cancer cells.
- Assessment of cell death mechanisms, including ER stress and signaling pathway activation (mTOR, IRE1α-JNK).
- Evaluation of synergistic effects of combined therapeutic interventions.
Main Results:
- HER2(+) breast cancers exhibit increased expression of ERAD pathway genes.
- Inhibition of ERAD induces irreversible ER stress and selective cell death in HER2(+) cancer cells.
- ERAD inhibition-induced cell death is partly mediated by enhanced HER2-mTOR signaling and increased proteotoxic burden.
- The IRE1α-JNK pathway is essential for ER stress-induced cell death and is suppressed in HER2(+) cancers by JNK phosphatases.
- Combined inhibition of ERAD and JNK phosphatases shows synergistic cytotoxicity specifically in HER2(+) breast cancer cells.
Conclusions:
- Targeting ERAD represents a promising strategy for HER2(+) breast cancer.
- Reactivating oncogene-induced stress by inhibiting adaptive stress pathways can overcome therapy resistance.
- Combined ERAD and JNK phosphatase inhibition offers a synergistic therapeutic approach for HER2-amplified, therapy-resistant breast cancers.
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