EGFR in Cancer: Signaling Mechanisms, Drugs, and Acquired Resistance

Uribe, Mary Luz; Marrocco, Ilaria; Yarden, Yosef

doi:10.3390/cancers13112748

Cited by 604HER2/EGFR in Cancer ResearchLung Cancer Treatments and MutationsCancer Mechanisms and Therapy

EGFR in Cancer: Signaling Mechanisms, Drugs, and Acquired Resistance

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Uribe, Mary Luz, Marrocco, Ilaria, Yarden, Yosef·2021·Cancers

DOI 10.3390/cancers13112748PMC PMC8197917

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Abstract

The epidermal growth factor receptor (EGFR) has served as the founding member of the large family of growth factor receptors harboring intrinsic tyrosine kinase function. High abundance of EGFR and large internal deletions are frequently observed in brain tumors, whereas point mutations and small insertions within the kinase domain are common in lung cancer. For these reasons EGFR and its preferred heterodimer partner, HER2/ERBB2, became popular targets of anti-cancer therapies. Nevertheless, EGFR research keeps revealing unexpected observations, which are reviewed herein. Once activated by a ligand, EGFR initiates a time-dependent series of molecular switches comprising downregulation of a large cohort of microRNAs, up-regulation of newly synthesized mRNAs, and covalent protein modifications, collectively controlling phenotype-determining genes. In addition to microRNAs, long non-coding RNAs and circular RNAs play critical roles in EGFR signaling. Along with driver mutations, EGFR drives metastasis in many ways. Paracrine loops comprising tumor and stromal cells enable EGFR to fuel invasion across tissue barriers, survival of clusters of circulating tumor cells, as well as colonization of distant organs. We conclude by listing all clinically approved anti-cancer drugs targeting either EGFR or HER2. Because emergence of drug resistance is nearly inevitable, we discuss the major evasion mechanisms.

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Activation of ErbB receptors promotes resistance to KRASG12C or MEK inhibitors in colorectal cancer.
“Activation of ErbB receptors has been shown to promote resistance to KRASG12C or MEK inhibitors in CRC”
From The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells (2022) · cites this paper as [58]
Combination therapies of lapatinib and either KRASG12C or MEK inhibitors provided more durable therapies in tumor models.
“whereby combination therapies of lapatinib and either KRASG12C or MEK inhibitors provided more durable therapies in tumor models (40, 58).”
From The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells (2022) · cites this paper as [58]
ErbB receptors are frequently altered in cancers.
“ErbB receptors are frequently altered in cancers”
From The drug efflux pump MDR1 promotes intrinsic and acquired resistance to PROTACs in cancer cells (2022) · cites this paper as [58]

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Fibroblast-secreted hepatocyte growth factor mediates epidermal growth factor receptor tyrosine kinase inhibitor resistance in triple-negative breast cancers through paracrine activation of Met
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Authors: Uribe, M. L., Marrocco, I., & Yarden, Y.
Affiliations: Weizmann Institute of Science (IL)
Corresponding author: Yarden, Yosef
ORCID: Uribe, Mary Luz
Marrocco, Ilaria
Yarden, Yosef
Venue: Cancers
Publisher: MDPI AG
Published: 2021-06-01
Volume: 13
Issue: 11
Pages: 2748
ISSN: 2072-6694 (ISSN-L)
DOI: 10.3390/cancers13112748
PMC: PMC8197917
OpenAlex: W3169321271
Cited by: 604
References: 159
Citations by year: 2026: 136 · 2025: 181 · 2024: 151 · 2023: 85 · 2022: 39 · 2021: 12
FWCI: 8.70
Type: journal article
Language: en
Open access: gold
doi.org
Licence: cc-by
creativecommons.org/licenses/by/4.0/ (vor)
Locations: Cancers (publishedVersion, cc-by)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
PubliCatt (Università Cattolica del Sacro Cuore) (submittedVersion, other-oa)
Funders: FP7 Ideas: European Research Council (740469)
Israel Science Foundation (1931/20)
Israel Cancer Research Fund (18-304-MI)
Samuel Waxman Cancer Research Foundation (432/2020)
Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (15)
Topics: Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
Health Sciences › Medicine › Pathology and Forensic Medicine › Cancer Mechanisms and Therapy
Keywords: EGFR, human epidermal growth factor receptor 2, tyrosine kinase signaling, EGFR mutation, microRNA, long non-coding RNA, circular RNA, metastasis, tumor stroma, circulating tumor cells, drug resistance, anti-EGFR therapy, HER2-targeted therapy, lung cancer, brain tumors

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EGFR in Cancer: Signaling Mechanisms, Drugs, and Acquired Resistance

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