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- Title
Exploring the Potential of Epiregulin and Amphiregulin as Prognostic, Predictive, and Therapeutic Targets in Colorectal Cancer.
- Authors
Guernsey-Biddle, Cara; High, Peyton; Carmon, Kendra S.
- Abstract
Simple Summary: Colorectal cancer (CRC) is the second-leading cause of cancer-related deaths in the United States, with a 14% five-year survival rate when metastasized. Current treatment options for metastatic CRC (mCRC) include combination chemotherapy regimens, immune checkpoint therapy, and monoclonal antibodies (mAbs), such as those targeting the epidermal growth factor receptor (EGFR). However, efficacy of these therapies is limited. EGFR-targeted mAbs extend survival only in a subset of mCRC patients (10–20%), in part due to drug resistance. Thus, additional biomarkers are required to identify responsive patients and to develop novel targeting strategies that will overcome resistance. This review aims to provide a comprehensive overview of EGFR ligands epiregulin (EREG) and amphiregulin (AREG) as prognostic, predictive, and therapeutic targets in CRC. The epidermal growth factor receptor (EGFR) plays a critical role in regulating essential cellular processes that are frequently hijacked to promote cancer. In colorectal cancer (CRC) in particular, the EGFR signaling pathway is frequently hyperactivated via receptor and/or ligand overexpression and downstream oncogenic mutations. Current EGFR-targeted therapies for metastatic CRC (mCRC) include the mAbs cetuximab and panitumumab. However, intrinsic and acquired resistance to EGFR-targeted mAbs are commonly observed. Thus, additional biomarkers are necessary to better understand patient sensitivity to EGFR-targeted therapies. Furthermore, therapeutic targeting of alternative EGFR pathway components may serve as one mechanism to overcome EGFR-targeted mAb resistance. In this review, we discuss the mounting evidence supporting EGFR ligands epiregulin (EREG) and amphiregulin (AREG), which are overexpressed in CRC with potential key roles in tumor progression, as predictive biomarkers for EGFR-targeted therapy sensitivity, as well as mediators of therapy resistance, though further studies are necessary to validate the prognostic roles and mechanisms by which these ligands contribute to resistance. Additionally, we review recent advances towards therapeutic targeting of EREG and AREG in cancer through the development and use of EREG- and AREG-targeted mAbs as well as antibody–drug conjugates (ADCs). We conclude with a discussion on the roadblocks to clinical implementation of EREG and AREG as biomarkers, as well as approaches to enhance the efficacy of current EREG- and AREG-targeted strategies.
- Subjects
EPIDERMAL growth factor receptors; IMMUNE checkpoint proteins; COLORECTAL cancer; PANITUMUMAB; AMPHIREGULIN; METASTATIC breast cancer
- Publication
Onco, 2024, Vol 4, Issue 4, p257
- ISSN
2673-7523
- Publication type
Academic Journal
- DOI
10.3390/onco4040019