Nuclear epidermal growth factor receptor as a therapeutic target
Benjamin Atwell1, Pavani Chalasani2,3, Joyce Schroeder1,3,4
1Department of Molecular and Cellular Biology, University of Arizona, Tucson, AZ 85721, USA.
Abstract:
Epidermal growth factor receptor (EGFR) is one of the most well-studied oncogenes with roles in proliferation, growth, metastasis, and therapeutic resistance. This intense study has led to the development of a range of targeted therapeutics including small-molecule tyrosine kinase inhibitors (TKIs), monoclonal antibodies, and nanobodies. These drugs are excellent at blocking the activation and kinase function of wild-type EGFR (wtEGFR) and several common EGFR mutants. These drugs have significantly improved outcomes for patients with cancers including head and neck, glioblastoma, colorectal, and non-small cell lung cancer (NSCLC). However, therapeutic resistance is often seen, resulting from acquired mutations or activation of compensatory signaling pathways. Additionally, these therapies are ineffective in tumors where EGFR is found predominantly in the nucleus, as can be found in triple negative breast cancer (TNBC). In TNBC, EGFR is subjected to alternative trafficking which drives the nuclear localization of the receptor. In the nucleus, EGFR interacts with several proteins to activate transcription, DNA repair, migration, and chemoresistance. Nuclear EGFR (nEGFR) correlates with metastatic disease and worse patient prognosis yet targeting its nuclear localization has proved difficult. This review provides an overview of current EGFR-targeted therapies and novel peptide-based therapies that block nEGFR, as well as their clinical applications and potential for use in oncology.
Insights
Epidermal growth factor receptor (EGFR) therapies show promise but face resistance. Novel peptide-based treatments targeting nuclear EGFR (nEGFR) offer new hope, especially for triple-negative breast cancer (TNBC).
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Epidermal growth factor receptor (EGFR) is a key oncogene implicated in cancer proliferation, metastasis, and therapeutic resistance.
- Current EGFR-targeted therapies, including TKIs and antibodies, are effective against wild-type and mutant EGFR but face challenges like acquired resistance and ineffectiveness in certain cancers such as triple-negative breast cancer (TNBC).
Purpose of the Study:
- To review current EGFR-targeted therapies and explore novel peptide-based therapies designed to block nuclear EGFR (nEGFR).
- To discuss the clinical applications and potential of these novel therapies in oncology, particularly for TNBC where EGFR exhibits nuclear localization.
Main Methods:
- Literature review of existing EGFR-targeted therapies and their mechanisms.
- Exploration of emerging peptide-based therapies targeting the nuclear localization and function of EGFR.
- Analysis of clinical data and potential applications in various cancer types.
Main Results:
- EGFR's role in nuclear functions like transcription, DNA repair, and chemoresistance in TNBC.
- Nuclear localization of EGFR (nEGFR) is associated with metastatic disease and poor prognosis.
- Novel peptide-based therapies demonstrate potential in blocking nEGFR activity.
Conclusions:
- Current EGFR therapies have limitations, especially in TNBC due to nuclear EGFR.
- Targeting nuclear EGFR presents a promising new strategy for overcoming therapeutic resistance.
- Peptide-based therapies offer a novel approach to inhibit nEGFR, with potential for improved cancer treatment outcomes.
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