ArticleProceedings of the National Academy of Sciences of the United States of America2015
HER2 missense mutations have distinct effects on oncogenic signaling and migration.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers.
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Who cites it
56 citing papers in PubMed, 82 citations in OpenAlex.
- Efficacy and Determinants of Response to HER Kinase Inhibition inCancer discovery · 2020Trial
- Trial
- Genetically engineered ErbB2 overexpression sensitizes organoid-derived tumors to checkpoint inhibition in a syngeneic model of gastric cancer.Journal for immunotherapy of cancer · 2026Article
- HER2-targeted therapies beyond breast cancer - an update.Nature reviews. Clinical oncology · 2024Review
- HER3 receptor and its role in the therapeutic management of metastatic breast cancer.Journal of translational medicine · 2024Review
- HER2 mutation as an emerging target in advanced breast cancer.Cancer science · 2024Review
- Genomic dissection and mutation-specific target discovery for breast cancer PIK3CA hotspot mutations.BMC genomics · 2024Article
- An in vitro CRISPR screen of cell-free DNA identifies apoptosis as the primary mediator of cell-free DNA release.Communications biology · 2024Article
- Rare subclonal sequencing of breast cancers indicates putative metastatic driver mutations are predominately acquired after dissemination.Genome medicine · 2024Article
- The uncharted role of HER2 mutant alleles in breast cancer.Oncotarget · 2023Article
- Resistance of Lung Cancer to EGFR-Specific Kinase Inhibitors: Activation of Bypass Pathways and Endogenous Mutators.Cancers · 2023Review
- Rare molecular subtypes of lung cancer.Nature reviews. Clinical oncology · 2023Review
- HER2 Expression in Peritoneal Dissemination of High-Grade Serous Ovarian Carcinoma: A Comparative Study of Immunohistochemical Reactivity Using Four HER2 Antibodies.Journal of clinical medicine · 2022Article
- Emerging Role of ERBB2 in Targeted Therapy for Metastatic Colorectal Cancer: Signaling Pathways to Therapeutic Strategies.Cancers · 2022Review
- HOXA5-Mediated Stabilization of IκBα Inhibits the NF-κB Pathway and Suppresses Malignant Transformation of Breast Epithelial Cells.Cancer research · 2022Article
- The role of HER2 alterations in clinicopathological and molecular characteristics of breast cancer and HER2-targeted therapies: a comprehensive review.Medical oncology (Northwood, London, England) · 2022Review
- Poziotinib Inhibits HER2-Mutant-Driven Therapeutic Resistance and Multiorgan Metastasis in Breast Cancer.Cancer research · 2022Article
- A novel treatment strategy of HER2-targeted therapy in combination with Everolimus for HR+/HER2- advanced breast cancer patients with HER2 mutations.Translational oncology · 2022Article
- HER2 G776S mutation promotes oncogenic potential in colorectal cancer cells when accompanied by loss of APC function.Scientific reports · 2022Article
- Integrated approach to functional analysis of an ERBB2 variant of unknown significance detected by a cancer gene panel test.Cellular oncology (Dordrecht, Netherlands) · 2022Article
Corrections and comments
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Authors and funding
23 authors at 6 institutions in 2 countries.
Funding
Abstract
Recurrent human epidermal growth factor receptor 2 (HER2) missense mutations have been reported in human cancers. These mutations occur primarily in the absence of HER2 gene amplification such that most HER2-mutant tumors are classified as "negative" by FISH or immunohistochemistry assays. It remains unclear whether nonamplified HER2 missense mutations are oncogenic and whether they are targets for HER2-directed therapies that are currently approved for the treatment of HER2 gene-amplified breast cancers. Here we functionally characterize HER2 kinase and extracellular domain mutations through gene editing of the endogenous loci in HER2 nonamplified human breast epithelial cells. In in vitro and in vivo assays, the majority of HER2 missense mutations do not impart detectable oncogenic changes. However, the HER2 V777L mutation increased biochemical pathway activation and, in the context of a PIK3CA mutation, enhanced migratory features in vitro. However, the V777L mutation did not alter in vivo tumorigenicity or sensitivity to HER2-directed therapies in proliferation assays. Our results suggest the oncogenicity and potential targeting of HER2 missense mutations should be considered in the context of cooperating genetic alterations and provide previously unidentified insights into functional analysis of HER2 mutations and strategies to target them.
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Registered trials
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 OpenQuestion graph.