ArticleBreast cancer research : BCR2019
Targeting promiscuous heterodimerization overcomes innate resistance to ERBB2 dimerization inhibitors in breast cancer.
Article in Breast cancer research : BCR, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 28 papers.
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Who cites it
28 citing papers in PubMed, 46 citations in OpenAlex.
- Special Issue "Molecular Research and Cellular Biology of Breast Cancer".International journal of molecular sciences · 2026Article
- Modeling acquired TKI resistance and effective combination therapeutic strategies in murine RET+ lung adenocarcinoma.Cancer letters · 2026Article
- Inclusion of JNK-independent drugs within multiagent chemotherapy improves response in relapsed high-risk neuroblastoma.Science advances · 2025Article
- Micromapping (μMap) of HER2 Across Human Breast Cancers: Photocatalytic Proximity Labeling Identifies Primary Resistance Mechanisms and Functional Interactors.bioRxiv : the preprint server for biology · 2025Article
- PDGFRα/β heterodimer activation negatively affects downstream ERK1/2 signaling and cellular proliferation.Nature communications · 2025Article
- Development of a novel anti-erythropoietin-producing hepatocellular receptor B6 monoclonal antibody EbBiochemistry and biophysics reports · 2025Article
- Anticancer Target Combinations: Network-Informed Signaling-Based Approach to Discovery.bioRxiv : the preprint server for biology · 2024Article
- Targeted dual degradation of HER2 and EGFR obliterates oncogenic signaling, overcomes therapy resistance, and inhibits metastatic lesions in HER2-positive breast cancer models.Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy · 2024Article
- Eph receptors and ephrins in cancer progression.Nature reviews. Cancer · 2024Review
- Identifying Lymph Node Metastasis-Related Factors in Breast Cancer Using Differential Modular and Mutational Structural Analysis.Interdisciplinary sciences, computational life sciences · 2023Article
- Targeting Epidermal Growth Factor Receptor for Cancer Treatment: Abolishing Both Kinase-Dependent and Kinase-Independent Functions of the Receptor.Pharmacological reviews · 2023Review
- An unanticipated discourse of HB-EGF with VANGL2 signaling during embryo implantation.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Memory of stochastic single-cell apoptotic signaling promotes chemoresistance in neuroblastoma.Science advances · 2023Article
- Control of cell state transitions.Nature · 2022Article
- Depleting receptor tyrosine kinases EGFR and HER2 overcomes resistance to EGFR inhibitors in colorectal cancer.Journal of experimental & clinical cancer research : CR · 2022Article
- Extensive conformational and physical plasticity protects HER2-HER3 tumorigenic signaling.Cell reports · 2022Article
- Functional signaling test identifies HER2 negative breast cancer patients who may benefit from c-Met and pan-HER combination therapy.Cell communication and signaling : CCS · 2022Article
- Identification of Synergistic Drug Combinations to Target KRAS-Driven Chemoradioresistant Cancers Utilizing Tumoroid Models of Colorectal Adenocarcinoma and Recurrent Glioblastoma.Frontiers in oncology · 2022Article
- Ultrasound-triggered herceptin liposomes for breast cancer therapy.Scientific reports · 2021Article
- The root cause of drug resistance in HER2-positive breast cancer and the therapeutic approaches to overcoming the resistance.Pharmacology & therapeutics · 2021Review
Corrections and comments
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Authors and funding
21 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundThe oncogenic receptor tyrosine kinase (RTK) ERBB2 is known to dimerize with other EGFR family members, particularly ERBB3, through which it potently activates PI3K signalling. Antibody-mediated inhibition of this ERBB2/ERBB3/PI3K axis has been a cornerstone of treatment for ERBB2-amplified breast cancer patients for two decades. However, the lack of response and the rapid onset of relapse in many patients now question the assumption that the ERBB2/ERBB3 heterodimer is the sole relevant effector target of these therapies.
methodsThrough a systematic protein-protein interaction screen, we have identified and validated alternative RTKs that interact with ERBB2. Using quantitative readouts of signalling pathway activation and cell proliferation, we have examined their influence upon the mechanism of trastuzumab- and pertuzumab-mediated inhibition of cell growth in ERBB2-amplified breast cancer cell lines and a patient-derived xenograft model.
resultsWe now demonstrate that inactivation of ERBB3/PI3K by these therapeutic antibodies is insufficient to inhibit the growth of ERBB2-amplified breast cancer cells. Instead, we show extensive promiscuity between ERBB2 and an array of RTKs from outside of the EGFR family. Paradoxically, pertuzumab also acts as an artificial ligand to promote ERBB2 activation and ERK signalling, through allosteric activation by a subset of these non-canonical RTKs. However, this unexpected activation mechanism also increases the sensitivity of the receptor network to the ERBB2 kinase inhibitor lapatinib, which in combination with pertuzumab, displays a synergistic effect in single-agent resistant cell lines and PDX models.
conclusionsThe interaction of ERBB2 with a number of non-canonical RTKs activates a compensatory signalling response following treatment with pertuzumab, although a counter-intuitive combination of ERBB2 antibody therapy and a kinase inhibitor can overcome this innate therapeutic resistance.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.