Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications

Iqbal, Nida; Iqbal, Naveed

doi:10.1155/2014/852748

Cited by 938 publications

(750 citation statements)

References 72 publications

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“…Overexpression of HER2 gene is found in about 20–30% breast cancer, and it is associated with aggressive growth and poor clinical outcomes. 1 Overexpression of HER2 may also be observed in other tumors such as ovary, endometrium, bladder, lung, colon, and head-neck tumors. 1 In breast cancer, HER2 is commonly recognized as a predictive factor and a therapeutic target.…”

Section: Introductionmentioning

confidence: 99%

“…1 Overexpression of HER2 may also be observed in other tumors such as ovary, endometrium, bladder, lung, colon, and head-neck tumors. 1 In breast cancer, HER2 is commonly recognized as a predictive factor and a therapeutic target. Since HER2 has no specific ligand, its antibodies usually inhibit tumor cells by blocking dimerization and activation of the receptor and mediating killing effect of immune system.…”

Section: Introductionmentioning

confidence: 99%

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Structural and functional characterization of MBS301, an afucosylated bispecific anti-HER2 antibody

Huang

Liu

et al. 2018

mAbs

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MBS301, a glyco-engineered bispecific anti-human epidermal growth factor receptor 2 (HER2) antibody with a typical IgG1 monoclonal antibody structure, was developed through dual-cell expression and in vitro assembling process. MBS301 consists of two half antibodies engineered from trastuzumab and pertuzumab, respectively. Integrity and purity profiles of MB301 indicated that the heterodimerization of the two half antibodies was successful. The high and similar melting temperatures (Tm1,72.0°C and Tm2, 84.8°C) of MBS301 compared with those of its parental monoclonal antibodies trastuzumab and pertuzumab (in-house made T-mab and P-mab, respectively) revealed its structural compactness. With computer-modeling experiments and Biacore binding and competition kinetics studies, the binding stoichiometry between MBS301 and HER2-ECD was determined to be 1:1 and the two arms of MBS301 were shown to bind to domains II and IV of HER2-ECD antigen simultaneously. MBS301 displayed synergistic bioactivities as the combination of T-mab and P-mab in vitro in multiple cancer cell lines and in vivo in xenograft mouse model studies, and showed more effective activity than T-mab or P-mab used individually. Moreover, fucose-knockout dramatically increased MBS301’s binding affinity to low affinity FcγRIIIa allotype 158F (KD = 2.35 × 10−7M) to near the high affinity level of allotype V158 (KD = 1.17 × 10−7M). This resulted in far more effective ADCC activity of MBS301 than the combination of T-mab and P-mab in killing HER2-positive cancer cells. Hence, a novel fully afucosylated anti-HER2 bispecific antibody with improved antitumor activities was generated and shown to have the potential to be used for treating HER2-positive but trastuzumab-resistant solid tumors.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structural and functional characterization of MBS301, an afucosylated bispecific anti-HER2 antibody

Huang

Liu

et al. 2018

mAbs

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“…These receptors regulate normal cell proliferation, survival, and differentiation via different signal transduction pathways 1. The gene encoding HER‐2 is located in chromosome 17, and codes for a 185‐kPa protein that functions as a transmembrane growth factor receptor 2.…”

Section: Introductionmentioning

confidence: 99%

Analysis of different HER‐2 mutations in breast cancer progression and drug resistance

Sun

Shi

Shen

et al. 2015

J Cellular Molecular Medi

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Studies over the last two decades have identified that amplified human epidermal growth factor receptor (HER‐2; c‐erbB‐2, neu) and its overexpression have been frequently implicated in the carcinogenesis and prognosis in a variety of solid tumours, especially breast cancer. Lots of painstaking efforts were invested on the HER‐2 targeted agents, and significantly improved outcome and prolonged the survival of patients. However, some patients classified as ‘HER‐2‐positive’ would be still resistant to the anti‐HER‐2 therapy. Various mechanisms of drug resistance have been illustrated and the alteration of HER‐2 was considered as a crucial mechanism. However, systematic researches in regard to the HER‐2 mutations and variants are still inadequate. Notably, the alterations of HER‐2 play an important role in drug resistance, but also have a potential association with the cancer risk. In this review, we summarize the possible mutations and focus on HER‐2 variants’ role in breast cancer tumourigenesis. Additionally, the alteration of HER‐2, as a potential mechanism of resistance to trastuzumab, is discussed here. We hope that HER‐2 related activating mutations could potentially offer more therapeutic opportunities to a broader range of patients than previously classified as HER‐2 overexpressed.

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“…These variants may be associated with ERBB2 protein overexpression, thus potential response to anti-Her2/neu (trastuzumab) in combination with other agents e.g. cetuximab and pertuzumab [59,60].…”

Section: Tp53 Showed the Highest Percentage Of Germline Inherited Mutmentioning

confidence: 99%

Genetic Variations of Selected Genes Using Target Deep Sequencing in Colorectal Cancer Patients

Farghal¹,

Saied²,

Ghaith³

et al. 2017

J Cancer Sci Ther

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Background: Colorectal carcinoma (CRC) is a burden problem in a developing country like Egypt since patients are usually admitted in late stage with bad prognosis and short overall survival. Because of genetic predisposition of CRC and introduction of advanced molecular techniques, efforts are directed to screen for potential pathogenic or disease-causing variants in CRC patients Methods: DNA was isolated from formalin fixed paraffin embedded tissue sections collected from 24 CRC confirmed diagnosed patients. TruSight CRC panel (Illumina) was used for detection of different variants in 15 genes. The generated reads were obtained from Illumina Miseq were clustered into single nucleotide polymorphism (SNPs) and small insertions/deletions (Indels). Further pathogenic variants with somatic and germline mutations were identified according to the recommended criteria. Some CRC patients were subjected to anti-EGFR target therapy.Results: Most of the variants were detected in TP53 gene 140 variants (65%); 105 short deletions none of them was pathogenic, 29 missense mutations and 6 SNPs at splicing sites. Next, ERBB2 has got 17 variants (8.8%) (missense and splicing), 8 of them were damaging disease causing variants. Besides, 16 pathogenic variants were identified in 12 patients (6 in TP53 and 7 in KRAS). Some pathogenic variants were not reported before in CRC e.g. TP53 C>A, rs121912654, Val157Phe. Additionally, patients carried different KRAS wild mutations showed variable response to anti-EGFR target therapy. Conclusion:The most affected pathway in CRC was TP53 pathway followed by ERBB2, NRAS, KRAS and PIK3CA genes. Variable response to target therapy suggested dependence on the type of pathogenic variant identified, also a possible role of ERBB2 which had a significant variant frequency.NRAS. The prevalence rate of TP53 mutation in Arab population is 52.5% compared to 47.5% in matched Western population [7]. TP53 mutations have roles in determining progression, invasiveness and also metastasis of CRC. So, CRC patients with mutant TP53 have more progressive phenotype and poorer survival than those with TP53 wild type [8]. The phosphatidylinositol 3-kinase/Akt/mammalian target of

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Human Epidermal Growth Factor Receptor 2 (HER2) in Cancers: Overexpression and Therapeutic Implications

Cited by 938 publications

References 72 publications

Structural and functional characterization of MBS301, an afucosylated bispecific anti-HER2 antibody

Structural and functional characterization of MBS301, an afucosylated bispecific anti-HER2 antibody

Analysis of different HER‐2 mutations in breast cancer progression and drug resistance

Genetic Variations of Selected Genes Using Target Deep Sequencing in Colorectal Cancer Patients

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