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Ref Type Journal Article
PMID (27697991)
Authors Zuo WJ, Jiang YZ, Wang YJ, Xu XE, Hu X, Liu GY, Wu J, Di GH, Yu KD, Shao ZM
Title Dual Characteristics of Novel HER2 Kinase Domain Mutations in Response to HER2-Targeted Therapies in Human Breast Cancer.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 22
Issue 19
Date 2016 Oct 01
URL
Abstract Text Somatic mutations in the tyrosine kinase domain of human epidermal growth factor receptor 2 (HER2) may be an alternative mechanism to HER2 activation and can affect the sensitivity toward HER2-targeted therapies. We aimed to investigate the prevalence, clinicopathologic characteristics, and functional relevance of novel HER2 mutations in breast cancer.We performed Sanger sequencing of all exons of the HER2 gene in 1,248 primary tumors and 18 paired metastatic samples. Novel HER2 mutations were functionally characterized.The total HER2 somatic mutation rate was 2.24% (28/1,248). Of the seven novel HER2 mutations, L768S and V773L were only detected in HER2-negative tumors, whereas K753E was found in HER2-positive disease. L768S and V773L mutations exhibited a significant increase in tyrosine kinase-specific activity and strongly increased the phosphorylation of signaling proteins in various cell lines. Xenograft experiments showed that NIH3T3 cells bearing the L768S and V773L mutations displayed more rapid growth. MCF10A, BT474, and MDA-MB-231 cells bearing the K753E mutation were resistant to lapatinib, but could be inhibited by neratinib. Finally, comparison of HER2 mutations in 18 pairs of primary and metastatic lesions revealed that the drug-resistant HER2 mutations (K753E and L755S) were enriched in metastatic lesions.HER2-negative breast cancer with activating mutations can benefit from HER2-targeted therapies. Meanwhile, mutations in the HER2 kinase domain might be a key mechanism of resistance to HER2-targeted therapy, and irreversible tyrosine kinase inhibitors such as neratinib may offer alternative treatment options. Clin Cancer Res; 22(19); 4859-69. ©2016 AACR.

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Molecular Profile Treatment Approach
ERBB2 K753E Neratinib
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
ERBB2 I655V missense no effect - predicted ERBB2 (HER2) I655V is a common Erbb2 (Her2) polymorphism (PMID: 21474413, PMID: 14578152) that lies within the transmembrane domain of the Erbb2 (Her2) protein (PMID: 18178548). I655V results in similar cell proliferation and viability levels to wild-type Erbb2 (Her2) in two different cell lines (PMID: 29533785), and similar structural morphology to wild-type Erbb2 in culture (PMID: 27697991), and therefore, is predicted to have no effect on Erbb2 (Her2) protein function.
ERBB2 K676R missense no effect ERBB2 (HER2) K676R lies within the juxtamembrane domain of the Erbb2 (Her2) protein (PMID: 30449325). K676R confers no effect to the Erbb2 (Her2) protein, resulting in kinase activity, phosphorylation, and cell morphology in culture similar to wild-type (PMID: 27697991).
ERBB2 K753E missense unknown ERBB2 (HER2) K753E lies within the protein kinase domain of the Erbb2 (Her2) protein (UniProt.org). K753E does not result in increased phosphorylation of Erbb2 (Her2) or downstream PLC-gamma, and results in similar tumor formation to wild-type Erbb2 (Her2) in mouse models, however, results in increased Egfr phosphorylation and is associated with resistance to some Erbb2 (Her2) inhibitors (PMID: 27697991, PMID: 29389942). Y
ERBB2 L768S missense gain of function ERBB2 (HER2) L768S lies within the protein kinase domain of the Erbb2 (Her2) protein (UniProt.org). L768S confers a gain of function to the Erbb2 (Her2) protein as demonstrated by increased tyrosine kinase activity and phosphorylation compared to wild-type, and abnormal cellular morphology in culture (PMID: 27697991).
ERBB2 Q680R missense no effect ERBB2 (HER2) Q680R lies within the juxtamembrane domain of the Erbb2 (Her2) protein (PMID: 30449325). Q680R confers no effect to the Erbb2 (Her2) protein, resulting in kinase activity, phosphorylation, and cell morphology in culture similar to wild-type (PMID: 27697991).
ERBB2 R647K missense no effect ERBB2 (HER2) R647K lies within the extracellular domain of the Erbb2 (Her2) protein (UniProt.org). R647K confers no effect to the Erbb2 (Her2) protein, resulting in kinase activity, phosphorylation, and cell morphology in culture similar to wild-type (PMID: 27697991).
ERBB2 V773L missense gain of function ERBB2 (HER2) V773L lies within the protein kinase domain of the Erbb2 (Her2) protein (UniProt.org). V773L confers a gain of function to the Erbb2 (Her2) protein as demonstrated by increased tyrosine kinase activity and phosphorylation compared to wild-type, and abnormal cellular morphology in culture (PMID: 27697991).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ERBB2 L768S breast cancer sensitive Lapatinib Preclinical - Cell culture Actionable In a preclinical study, transformed human breast cells expressing ERBB2 (HER2) L768S were sensitive to Tykerb (lapatinib) in culture, resulting in decreased colony formation (PMID: 27697991). 27697991
ERBB2 V773L breast cancer sensitive Lapatinib Preclinical - Cell culture Actionable In a preclinical study, transformed human breast cells expressing ERBB2 (HER2) V773L were sensitive to Tykerb (lapatinib) in culture, resulting in decreased colony formation (PMID: 27697991). 27697991
ERBB2 V773L breast cancer sensitive Trastuzumab Preclinical - Cell culture Actionable In a preclinical study, transformed human breast cells expressing ERBB2 (HER2) V773L were sensitive to Herceptin (trastuzumab) in culture, resulting in decreased colony formation (PMID: 27697991). 27697991
ERBB2 K753E breast cancer resistant Trastuzumab Preclinical - Cell culture Actionable In a preclinical study, transformed human breast cells expressing ERBB2 (HER2) K753E were resistant to Herceptin (trastuzumab) in culture (PMID: 27697991). 27697991
ERBB2 V773L breast cancer sensitive Neratinib Preclinical - Cell culture Actionable In a preclinical study, transformed human breast cells expressing ERBB2 (HER2) V773L were sensitive to Nerlynx (nerlatinib) in culture, resulting in decreased colony formation (PMID: 27697991). 27697991
ERBB2 L768S breast cancer sensitive Trastuzumab Preclinical - Cell culture Actionable In a preclinical study, transformed human breast cells expressing ERBB2 (HER2) L768S were sensitive to Herceptin (trastuzumab) in culture, resulting in decreased colony formation (PMID: 27697991). 27697991
ERBB2 K753E breast cancer sensitive Neratinib Preclinical - Cell culture Actionable In a preclinical study, transformed human breast cells expressing ERBB2 (HER2) K753 were sensitive to Nerlynx (neratinib) in culture, resulting in decreased colony formation (PMID: 27697991). 27697991
ERBB2 L768S breast cancer sensitive Neratinib Preclinical - Cell culture Actionable In a preclinical study, transformed human breast cells expressing ERBB2 (HER2) L768S were sensitive to Nerlynx (neratinib) in culture, resulting in decreased colony formation (PMID: 27697991). 27697991
ERBB2 K753E breast cancer resistant Lapatinib Preclinical - Cell culture Actionable In a preclinical study, transformed human breast cells expressing ERBB2 (HER2) K753E were resistant to Tykerb (lapatinib) in culture (PMID: 27697991). 27697991