Activating human epidermal growth factor receptor 2 (HER2) gene mutation in bone metastases from breast cancer

Christgen, Matthias; Bartels, Stephan; Luft, Angelina; Persing, Sascha; Henkel, Daniel; Lehmann, Ulrich; Kreipe, Hans

doi:10.1007/s00428-018-2414-1

Cited by 18 publications

(14 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To address whether insertion of the ICD region can improve the immunogenicity of the HER2 antigen, we designed two novel HER2 antigens that contain the ICD region. Since the tyrosine kinase domain in the ICD region (a.a. 720–976) has been associated with oncogenic potential, it was disrupted by removing a.a. 703–994 or a.a. 780–919 [ 34 ], resulting in K965 or K1117, which were named based on the total antigen length ( Figure 1 A,B). The adenoviral vectors (Ad) carrying the engineered HER2 antigens were constructed by restriction enzyme cloning and homologous recombination using the BJ5183 E. coli strain [ 35 ].…”

Section: Resultsmentioning

confidence: 99%

Enhanced Immunogenicity of Engineered HER2 Antigens Potentiates Antitumor Immune Responses

et al. 2020

View full text Add to dashboard Cite

For cancer vaccines, the selection of optimal tumor-associated antigens (TAAs) that can maximize the immunogenicity of the vaccine without causing unwanted adverse effects is challenging. In this study, we developed two engineered Human epidermal growth factor receptor 2 (HER2) antigens, K965 and K1117, and compared their immunogenicity to a previously reported truncated HER2 antigen, K684, within a B cell and monocyte-based vaccine (BVAC). We found that BVAC-K965 and BVAC-K1117 induced comparable antigen-specific antibody responses and antigen-specific T cell responses to BVAC-K684. Interestingly, BVAC-K1117 induced more potent antitumor activity than the other vaccines in murine CT26-HER2 tumor models. In addition, BVAC-K1117 showed enhanced antitumor effects against truncated p95HER2-expressing CT26 tumors compared to BVAC-K965 and BVAC-K684 based on the survival analysis by inducing T cell responses against intracellular domain (ICD) epitopes. The increased ICD epitope-specific T cell responses induced by BVAC-K1117 compared to BVAC-K965 and BVAC-K684 were recapitulated in human leukocyte antigen (HLA)-untyped human PBMCs and HLA-A*0201 PBMCs. Furthermore, we also observed synergistic antitumor effects between BVAC-K1117 and anti-PD-L1 antibody treatment against CT26-HER2 tumors. Collectively, our findings demonstrate that inclusion of a sufficient number of ICD epitopes of HER2 in cellular vaccines can improve the antitumor activity of the vaccine and provide a way to optimize the efficacy of anticancer cellular vaccines targeting HER2.

show abstract

Section: Resultsmentioning

confidence: 99%

Enhanced Immunogenicity of Engineered HER2 Antigens Potentiates Antitumor Immune Responses

et al. 2020

View full text Add to dashboard Cite

show abstract

“… 216 Overexpression of EGFR and HER2 protein and amplification of HER2 oncogene play an important role in carcinogenesis, associated with breast, lung, gastric, ovarian, endometrial, and bladder cancer. 219 – 222 HER2 is also related to increased recurrence and poor prognosis in some cancers. 223 Thus, EGFR and HER2 are promising targets for treatment of cancer.…”

Section: Methodsmentioning

confidence: 99%

Targeted therapies in gynecological cancers: a comprehensive review of clinical evidence

Wang

Peng

et al. 2020

Sig Transduct Target Ther

114

View full text Add to dashboard Cite

Advanced and recurrent gynecological cancers are associated with poor prognosis and lack of effective treatment. The developments of the molecular mechanisms on cancer progression provide insight into novel targeted therapies, which are emerging as groundbreaking and promising cancer treatment strategies. In gynecologic malignancies, potential therapeutic targeted agents include antiangiogenic agents, poly (ADP-ribose) polymerase (PARP) inhibitors, tumor-intrinsic signaling pathway inhibitors, selective estrogen receptor downregulators, and immune checkpoint inhibitors. In this article, we provide a comprehensive review of the clinical evidence of targeted agents in gynecological cancers and discuss the future implication.

show abstract

“…Residue V777L, located in exon 20 (at the C-terminal tail of the C-α helix), is involved in TK activity. is activating mutation promotes the TK activity of HER2, increasing the phosphorylation of signaling proteins such as HER2, HER3, EGFR, and ERK, and the transformation of breast epithelial cells [29,33,40,45,60]. is mutation causes transcriptional activation in most tumors affected by this mutation, which usually occurs independently of HER2 gene activation [60].…”

Section: Mutations In the Tyrosine Kinase Domainmentioning

confidence: 99%

“…is activating mutation promotes the TK activity of HER2, increasing the phosphorylation of signaling proteins such as HER2, HER3, EGFR, and ERK, and the transformation of breast epithelial cells [29,33,40,45,60]. is mutation causes transcriptional activation in most tumors affected by this mutation, which usually occurs independently of HER2 gene activation [60]. In effect, cases have been described in breast cancer cell lines in which increased endogenous expression levels of HER2 V777L activated signal transduction pathways, but this did not significantly increase tumor growth [61].…”

Section: Mutations In the Tyrosine Kinase Domainmentioning

confidence: 99%

Somatic Mutations in HER2 and Implications for Current Treatment Paradigms in HER2-Positive Breast Cancer

Gaibar

Beltrán

Romero‐Lorca

et al. 2020

Journal of Oncology

View full text Add to dashboard Cite

In one of every four or five cases of breast cancer, the human epidermal growth factor receptor-2 (HER2) gene is overexpressed. These carcinomas are known as HER2-positive. HER2 overexpression is linked to an aggressive phenotype and a lower rate of disease-free and overall survival. Drugs such as trastuzumab, pertuzumab, lapatinib, neratinib, and the more recent afatinib target the deregulation of HER2 expression. Some authors have attributed somatic mutations in HER2, a role in resistance to anti-HER2 therapy as differential regulation of HER2 has been observed among patients. Recently, studies in metastatic ER + tumors suggest that some HER2 mutations emerge as a mechanism of acquired resistance to endocrine therapy. In an effort to identify possible biomarkers of the efficacy of anti-HER2 therapy, we here review the known single-nucleotide polymorphisms (SNPs) of the HER2 gene found in HER2-positive breast cancer patients and their relationship with clinical outcomes. Information was recompiled on 11 somatic HER2 SNPs. Seven polymorphisms are located in the tyrosine kinase domain region of the gene contrasting with the low number of mutations found in extracellular and transmembrane areas. HER2-positive patients carrying S310F, S310Y, R678Q, D769H, or I767M mutations seem good candidates for anti-HER2 therapy as they show favorable outcomes and a good response to current pharmacological treatments. Carrying the L755S or D769Y mutation could also confer benefits when receiving neratinib or afatinib. By contrast, patients with mutations L755S, V842I, K753I, or D769Y do not seem to benefit from trastuzumab. Resistance to lapatinib has been reported in patients with L755S, V842I, and K753I. These data suggest that exploring HER2 SNPs in each patient could help individualize anti-HER2 therapies. Advances in our understanding of the genetics of the HER2 gene and its relations with the efficacy of anti-HER2 treatments are needed to improve the outcomes of patients with this aggressive breast cancer.

show abstract

Activating human epidermal growth factor receptor 2 (HER2) gene mutation in bone metastases from breast cancer

Cited by 18 publications

References 28 publications

Enhanced Immunogenicity of Engineered HER2 Antigens Potentiates Antitumor Immune Responses

Enhanced Immunogenicity of Engineered HER2 Antigens Potentiates Antitumor Immune Responses

Targeted therapies in gynecological cancers: a comprehensive review of clinical evidence

Somatic Mutations in HER2 and Implications for Current Treatment Paradigms in HER2-Positive Breast Cancer

Contact Info

Product

Resources

About