Activating HER2 mutations in HER2 gene amplification negative breast cancer

By R. Bose, Shyam M. Kavuri, Adam C. Searleman, W. Shen, D. Shen, Daniel C. Koboldt, J. Monsey, Nicholas J. Goel, Adam B Aronson, Shunqiang Li and 4 more. Cancer Discovery, 2012

800 citations recorded by the source corpus.

Data from eight breast cancer genome sequencing projects identified 25 patients with HER2 somatic mutations in cancers lacking HER2 gene amplification. To determine the phenotype of these mutations, we functionally characterized thirteen HER2 mutations using in vitro kinase assays, protein structure analysis, cell culture and xenograft experiments. Seven of these mutations are activating mutations, including G309A, D769H, D769Y, V777L, P780ins, V842I, and R896C. HER2 in-frame deletion 755-759, which is homologous to EGFR exon 19 in-frame deletions, had a neomorphic phenotype with increased phosphorylation of EGFR or HER3. L755S produced lapatinib resistance, but was not an activating mutation in our experimental systems. All of these mutations were sensitive to the irreversible kinase inhibitor, neratinib. These findings demonstrate that HER2 somatic mutation is an alternative mechanism to activate HER2 in breast cancer and they validate HER2 somatic mutations as drug targets for breast cancer treatment.

Subfields: Cancer Research, Oncology

View Paper: https://www.semanticscholar.org/paper/e17be32c3044cc1e7a5f8ac4e5bac3794b685d74

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Citations in the corpus

Comprehensive Molecular Characterization of Urothelial Bladder Carcinoma (2014, neutral): “Solit (23), Oregon Health and Science University, Department of Urology - Theresa Koppie(24), Weill Medical College of Cornell University - Brian Robinson(32), National Institute of Environmental Health Sciences - Dmitry Gordenin(33), David Fargo(33), Leszek Klimczak(33), Steven Roberts(33), Optimum”
Pathogenic germline variants in 10,389 adult cancers (2018, background): “Activating mutations tend to couple with upregulation of the oncogenes, as seen for RET MEN2 alleles and MET p.H1112R in our cohort (Figure 4B) and somatic mutations of receptor tyrosine kinases (Bose et al., 2013).”
OncoKB: A Precision Oncology Knowledge Base (2017, background): “A more complex example of Level 3 alterations are ERBB2 missense mutations that are present in a minority of a broad range of human cancers 30 and often arise in patients without ERBB2 amplification or HER2 protein overexpression 31 .”