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Cited by 1,048HER2/EGFR in Cancer ResearchLung Cancer Treatments and MutationsCancer Mechanisms and Therapy

The DOI matches its Crossref record; 223 of the 227 references it cites were found in a registry or an index; none of the 199 sources its claims cite is checked for support yet.

ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics

Open access
Arteaga, Carlos L., Engelman, Jeffrey A.·2014·Cancer Cell
DOI 10.1016/j.ccr.2014.02.025PMC PMC4018830
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Abstract

ERBB receptors were linked to human cancer pathogenesis approximately three decades ago. Biomedical investigators have since developed substantial understanding of the biology underlying the dependence of cancers on aberrant ERBB receptor signaling. An array of cancer-associated genetic alterations in ERBB receptors has also been identified. These findings have led to the discovery and development of mechanism-based therapies targeting ERBB receptors that have improved outcome for many cancer patients. In this Perspective, we discuss current paradigms of targeting ERBB receptors with cancer therapeutics and our understanding of mechanisms of action and resistance to these drugs. As current strategies still have limitations, we also discuss challenges and opportunities that lie ahead as basic scientists and clinical investigators work toward more breakthroughs.

Overview

AI snapshot

Written from the paper’s full text.

TL;DR

This Perspective reviews how ERBB receptor alterations (EGFR, HER2, HER3, HER4) drive cancer, how mechanism-based inhibitors work, and how resistance emerges. It argues that overcoming resistance will require combinations targeting the oncogene plus bypass tracks, with attention to tumor evolution and trial design.

Key findings

  • HER2 amplification occurs in about 20% of breast cancers and is linked to poor outcome; HER2 mutations are found in several cancers, mostly without HER2 gene amplification, and are resistant to lapatinib/trastuzumab but sensitive to neratinib.
  • Activating EGFR mutations define a subset of NSCLC highly responsive to EGFR TKIs, with RECIST response rates of ~55%–75%; mutations are found in ~8%–10% of Caucasians and at higher proportion in East Asians.
  • Acquired EGFR TKI resistance commonly involves EGFR T790M, present in at least 50% of biopsies from patients with acquired resistance and detectable in ~35% of pre-treatment biopsies by highly sensitive methods.
  • PI3K/AKT pathway alterations occur in approximately 30% of HER2+ breast cancers and can confer resistance to HER2 inhibitors; bypass RTK activation (e.g., MET, IGF-1R, AXL, HER3) and apoptosis/cell-cycle defects also mediate resistance.

Methods

  • Design: narrative Perspective/review, not a primary experimental study; it synthesizes preclinical models, clinical trials, and prior literature on ERBB biology and therapeutics.
  • Data/sample: no new patient cohort or dataset; examples include transgenic mouse models, cell lines, xenografts, clinical trials, and biopsy programs cited from the literature.
  • Main analysis: conceptual synthesis of ERBB oncogene discovery, downstream signaling, mechanisms of action of EGFR/HER2/HER3 inhibitors, resistance mechanisms, and combination strategies.

Limitations

  • The paper states that many laboratory resistance studies model single-agent therapy, whereas HER2-directed therapies and EGFR antibodies are often used with chemotherapy in the clinic, so selective pressures may not be recapitulated.
  • It states that correlative clinical trials often include chemotherapy as a variable not always considered, and resistance to HER2 antagonist combinations has not been widely modeled.
  • It notes that many RTK-mediated resistance mechanisms are measured mainly by protein assays (e.g., IHC for IGF-1R, AXL, EphA2), which do not prove causality; single biopsies may not capture all resistant clones across metastatic sites.
  • Evident from the text: as a Perspective, it lacks systematic search methods, formal risk-of-bias assessment, or meta-analysis, and reports no new primary outcomes.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.ccr.2014.02.025

Cites

223 of 223 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Verification

Claims the paper makes

0 of 199 cited sources checked · 0 supported · 0 flagged

Show all 122 claims

  • Probably not a substantial claim. 23
  • It may state two separate claims as one. 58
77 of 77

  • The paper relies on this without support.

    Mutant KRAS directly activates ERK.

    “However, since mutant KRAS directly activates ERK, cetuximab fails to suppress ERK in these cancers, likely explaining the lack of clinical activity (Ebi et al., 2011).”

  • The paper relies on this without support.

    Other than the immune effects of ERBB antibodies, most of the activity of these drugs is due to suppression of downstream signaling, particularly PI3K/AKT and MEK/ERK.

    “Other than the immune effects of ERBB antibodies, it is believed that most of activity of these drugs is due to suppression of downstream signaling, particularly PI3K/AKT and MEK/ERK.”

  • The paper relies on this without support.

    The antitumor activity of HER2 inhibitors depends on inhibition of PI3K-AKT downstream of HER2.

    “It is generally accepted that the antitumor activity of HER2 inhibitors depends on inhibition of PI3K-AKT downstream of HER2.”

  • The paper relies on this without support.

    Inhibition of a driver oncogene such as EGFR and HER2 results in proliferation arrest and apoptosis.

    “Inhibition of a driver oncogene such as EGFR and HER2 results in proliferation arrest and apoptosis.”

  • The paper relies on this without support.

    HER2 mutations in HER2 gene-amplified breast tumors are very rare.

    “To the best of our knowledge, HER2 mutations in HER2 gene-amplified breast tumors are very rare.”

  • The paper relies on this without support.

    At least 50% of biopsies from patients with acquired resistance harbor the T790M mutation.

    “At least 50% of biopsies from patients with acquired resistance harbor the T790M mutation.”

  • The paper relies on this without support.

    All currently available HER2 inhibitors target or exploit mechanisms of HER2 function.

    “All currently available HER2 inhibitors target or exploit mechanisms of HER2 function.”

  • The paper relies on this without support.

    HER2-amplified breast cancers vary with respect to their addiction to HER2 signaling, although they are grouped together using clinical criteria (FISH, IHC) for HER2 overexpression.

    “We also recognize that HER2-amplified breast cancers vary with respect to their addiction to HER2 signaling, although they are grouped together using clinical criteria (FISH, IHC) for HER2 overexpression.”

  • The paper relies on this without support.

    The presence of KRAS mutations predicts for lack of initial response to cetuximab.

    “As the presence of KRAS mutations predicts for lack of initial response to cetuximab, these findings underscore the convergence of intrinsic and acquired resistance mechanisms.”

  • The paper relies on this without support.

    There are a large number of potential resistance mechanisms.

    “the large number of potential resistance mechanisms will likely necessitate the use of more drugs than will be tolerable if they are all delivered simultaneously, and each drug is dosed to achieve continual target suppression.”

  • The authors state this as an assumption.

    Drug-resistant HER2+ residual cancers in the breast harbor targetable genomic alterations causally associated with resistance to neoadjuvant anti-HER2 therapy.

    “we propose ‘drug-resistant’ HER2+ residual cancers in the breast harbor targetable genomic alterations causally associated with resistance to neoadjuvant anti-HER2 therapy (Figure 4).”
11 of 11

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Third-generation EGFR inhibitor is named inconsistently

    Minor

    The discussion calls the inhibitor "CLO-1686," while the cited clinical-trial reference names it "CO-1686."

1 of 1

Citations

Cites

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Show all 227 references

4 of the 227 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. Ranson, 2013, AZD9291: an irreversible, potent and selective tyrosine kinase inhibitor (TKI) of activating (EGFRm+) and resistance (T790M) mutations in advanced NSCLC, J. Thorac. Oncol., 8, s389

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Metadata

Authors
Arteaga, C. L., & Engelman, J. A.
Affiliations
  • Vanderbilt University (US)
  • Harvard University (US)
Corresponding author
  • Arteaga, Carlos L.
  • Engelman, Jeffrey A.
ORCID
Venue
Cancer Cell
Publisher
Elsevier BV
Published
2014-03
Volume
25
Issue
3
Pages
282-303
ISSN
1535-6108 (ISSN-L)
DOI
10.1016/j.ccr.2014.02.025
PMC
PMC4018830
OpenAlex
W2037690883
Cited by
1,048
References
227
Citations by year
2026: 50 · 2025: 65 · 2024: 83 · 2023: 92 · 2022: 98 · 2021: 122 · 2020: 83 · 2019: 89 · 2018: 90 · 2017: 99 · 2016: 75 · 2015: 80 · 2014: 21
FWCI
10.41
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Cancer Institute (P50 CA98131, R01 CA80195, P50CA127003, P30 CA 68485, R01CA080195, R01 CA140954, P50CA098131, P30CA068485, R01CA164273, R01CA137008)
Topics
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Mechanisms and Therapy
Keywords
ErbB receptors, HER family, oncogene discovery, cancer therapeutics, drug resistance, genetic alterations, targeted cancer therapy, mechanism of action
MeSH terms
Animals, Humans, Neoplasms, Signal Transduction, Erb-b2 Receptor Tyrosine Kinases, Drug Resistance, Neoplasm, Receptor, ErbB-3, Mice, Antibodies, Monoclonal, Humanized, ErbB Receptors, Receptor, ErbB-4

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