PROteolysis TArgeting Chimera (PROTAC) Estrogen Receptor Degraders for Treatment of Estrogen Receptor-Positive
Erika P Hamilton1, Rinath M Jeselsohn2, Linda T Vahdat3,4
1Breast Cancer Research Program, Sarah Cannon Research Institute, 335 24th Avenue North, Suite 300, Nashville, TN, 37203, USA. erika.hamilton@scri.com.
Abstract:
The estrogen receptor (ER) signaling pathway is a key driver of breast cancer, primarily through the activation of genes that promote tumor cell survival and growth. The recommended first-line treatment for ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer is endocrine therapy plus a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. However, most patients experience disease progression, and there is no clear standard of care in the second-line setting. Thus, novel treatments in the advanced setting are needed. In this narrative review, we describe the unique mechanisms of action of a new class of drugs called PROteolysis TArgeting Chimera (PROTAC) ER degraders. Unlike other ER-targeted therapies, these small molecules harness the body's primary intracellular natural protein disposal machinery, the ubiquitin-proteasome system, to directly induce ER degradation. Vepdegestrant (ARV-471) is the furthest advanced PROTAC ER degrader currently in clinical development. Preclinical data demonstrate increased tumor growth inhibition with vepdegestrant alone or in combination with CDK4/6 inhibitors compared with the selective ER degrader fulvestrant. In a first-in-human phase 1/2 clinical study, vepdegestrant administered orally as monotherapy or in combination with palbociclib showed promising clinical activity and a favorable safety profile in patients with heavily pretreated ER+/HER2- advanced breast cancer. Several other PROTAC ER degraders (AC699, ERD-3111, ERD-4001, and HP568) are in early development and have demonstrated activity in preclinical breast cancer models, with some recently entering clinical trials. The data highlight the potential for PROTAC ER degraders to be a new backbone therapy in breast cancer.
Insights
New PROteolysis TArgeting Chimera (PROTAC) ER degraders offer a novel approach to treating advanced ER-positive breast cancer by directly degrading the estrogen receptor (ER). Clinical studies show promising activity and safety for vepdegestrant, a leading PROTAC ER degrader.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Estrogen receptor (ER) signaling drives ER-positive breast cancer, with current treatments like endocrine therapy plus CDK4/6 inhibitors often failing in advanced stages.
- Limited treatment options exist for patients with ER-positive/HER2- advanced or metastatic breast cancer who progress on first-line therapy.
- Novel therapeutic strategies are urgently needed to overcome treatment resistance and improve outcomes in advanced breast cancer.
Purpose of the Study:
- To review the mechanisms of action of PROteolysis TArgeting Chimera (PROTAC) ER degraders.
- To highlight the clinical development and potential of vepdegestrant (ARV-471) as a novel treatment for advanced ER-positive breast cancer.
- To discuss the broader potential of PROTAC ER degraders as a new therapeutic backbone.
Main Methods:
- Narrative review of existing preclinical and clinical data on PROTAC ER degraders.
- Focus on vepdegestrant's mechanism, preclinical efficacy, and Phase 1/2 clinical trial results.
- Overview of other PROTAC ER degraders in early development.
Main Results:
- PROTAC ER degraders utilize the ubiquitin-proteasome system to induce direct ER degradation, distinct from other ER-targeted therapies.
- Vepdegestrant demonstrated superior tumor growth inhibition compared to fulvestrant in preclinical models and showed promising clinical activity and safety in heavily pretreated patients.
- Several other PROTAC ER degraders are in early development, with some entering clinical trials and showing preclinical activity.
Conclusions:
- PROTAC ER degraders represent a promising new class of drugs for advanced ER-positive breast cancer.
- Vepdegestrant shows significant potential as a monotherapy or in combination regimens.
- Further clinical investigation of PROTAC ER degraders is warranted to establish their role as a backbone therapy.
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