HER2 shedding and serum HER2 extracellular domain: Biology and clinical utility in breast cancer

Tsé, Chantal; Gauchez, Anne-Sophie; Jacot, William; Lamy, Pierre‐Jean

doi:10.1016/j.ctrv.2011.03.008

Cited by 116 publications

(92 citation statements)

References 96 publications

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“…In the case of Trastuzumab, the epitope targeted by the antibody can be lost and shedding of receptor is also expected to limit the efficacy of this class of agent (24, 25). Similarly, there is evidence of selection to a state of HER2-negativity (23).…”

Section: Introductionmentioning

confidence: 99%

CDK4/6 inhibition provides a potent adjunct to Her2-targeted therapies in preclinical breast cancer models

2014

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In spite of the efficacy of Her2-targeted therapies, recurrence and progression remain a challenge for treatment of Her2 positive breast cancer. CDK4/6 controls pathway downstream of Her2, Inhibition of these kinases could represent an important therapeutic approach to augment the effectiveness of standard therapies. In models of acquired resistance to Her2-targeted therapies, Cyclin D1 was inappropriately activated and CDK4/6 inhibition was effective at blocking proliferation by targeting this common pathway associated with resistance. These data were recapitulated in Her2 positive xenografts. Furthermore, in a series of 35 primary breast tumor explants, treatment with PD-0332991 resulted in a greater than 4-fold suppression of the Ki67. The effects of CDK4/6 inhibition were dependent on an intact RB-pathway, and consonantly, loss of RB and high-levels of p16 were associated with resistance to CDK4/6 inhibition. Combination studies illustrated that CDK4/6 inhibition is cooperative with multiple Her2-targeted agents and provides a complementary mechanism of action to T-DM1 to efficiently suppresses the proliferation of residual Her2-positive tumor cell populations that survive T-DM1. Together, these data indicate CDK4/6 is a viable therapeutic target that functions downstream of Her2, and tissue based markers are available to direct rational utilization of CDK4/6 inhibitors in combination with Her2-targeted agents.

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Section: Introductionmentioning

confidence: 99%

CDK4/6 inhibition provides a potent adjunct to Her2-targeted therapies in preclinical breast cancer models

2014

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“…31 We thus hypothesized that vaccine-transfected muscle cells might be the source of the neu protein, otherwise not present in a wild-type mouse. As happens normally, EC may be shed from transfected muscle cell membranes, 32 form complexes with vaccine-induced anti-neu antibodies, and accumulate in the milk and be passed to the pups, triggering an active immune response. To confirm this hypothesis, an ELISA assay was set up to detect EC -IgG immune complexes that were found in the sera and milk of ECTM mothers.…”

Section: Discussionmentioning

confidence: 99%

Antitumor immunization of mothers delays tumor development in cancer-prone offspring

et al. 2015

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Abbreviations: Amot; Angiomotin p80; BALB-neuT mice; BALB/c mice heterozygous for the transforming form of the neu transgene; BKO mice; BALB/c female mice KO for the mIg chain; ECTM; extracellular and transmembrane; FcgKO mice; BALB/c mice KO for the Fc-gamma I/III receptors; FcgRI/III; Fc-gamma I/III receptors; IFNg; interferon gamma; KO; knockout; LNs; lymph nodes; RSI; rate of stimulation index; SFU; spot-forming unit; SPC; splenocytes; Treg; T-regulatory cellMaternal immunization is successfully applied against some life-threatening infectious diseases as it can protect the mother and her offspring through the passive transfer of maternal antibodies. Here, we sought to evaluate whether the concept of maternal immunization could also be applied to cancer immune-prevention. We have previously shown that antibodies induced by DNA vaccination against rat Her2 (neu) protect heterozygous neu-transgenic female (BALB-neuT) mice from autochthonous mammary tumor development. We, herein, seek to evaluate whether a similar maternal immunization can confer antitumor protection to BALB-neuT offspring. Significantly extended tumor-free survival was observed in BALB-neuT offspring born and fed by mothers vaccinated against neu, as compared to controls. Maternally derived anti-neu immunoglobulin G (IgG) was successfully transferred from mothers to newborns and was responsible for the protective effect. Vaccinated mothers and offspring also developed active immunity against neu as revealed by the presence of T-cell-mediated cytotoxicity against the neu immunodominant peptide. This active response was due to the milk transfer of immune complexes that were formed between the neu extracellular domain, shed from vaccinetransfected muscle cells, and the anti-neu IgG induced by the vaccine. These findings show that maternal immunization has the potential to hamper mammary cancer in genetically predestinated offspring and to develop into applications against lethal neonatal cancer diseases for which therapeutic options are currently unavailable.

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“…Trastuzumab is a humanized mAb that binds domain IV of the extracellular domain of the HER2 receptor, preventing activation of its intracellular tyrosine kinase (53, 54). Trastuzumab has several possible mechanisms of action, including prevention of HER2 receptor dimerization, increased endocytosis of the receptor, and inhibition of the generation of a constitutively active truncated intracellular HER2 molecule (53, 55). A phase II trial evaluated trastuzumab in combination with paclitaxel (Taxol®) and cisplatin (56).…”

Section: Her2 Inhibitorsmentioning

confidence: 99%

HER2 as a Therapeutic Target in Head and Neck Squamous Cell Carcinoma

Pollock

Grandis

2015

Clinical Cancer Research

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The majority of patients with head and neck squamous cell carcinoma (HNSCC) present with advanced-stage disease. Current standard of care is surgery followed by adjuvant radiation therapy with or without chemotherapy or chemoradiation alone. The addition of cetuximab for the treatment of patients with locally advanced or recurrent/metastatic HNSCC has improved overall survival and locoregional control; however, responses are often modest, and treatment resistance is common. A variety of therapeutic strategies are being explored to overcome cetuximab resistance by blocking candidate proteins implicated in resistance mechanisms such as HER2. Several HER2 inhibitors are in clinical development for HNSCC, and HER2-targeted therapy has been approved for several cancers. This review focuses on the biology of HER2, its role in cancer development, and the rationale for clinical investigation of HER2 targeting in HNSCC.

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HER2 shedding and serum HER2 extracellular domain: Biology and clinical utility in breast cancer

Cited by 116 publications

References 96 publications

CDK4/6 inhibition provides a potent adjunct to Her2-targeted therapies in preclinical breast cancer models

CDK4/6 inhibition provides a potent adjunct to Her2-targeted therapies in preclinical breast cancer models

Antitumor immunization of mothers delays tumor development in cancer-prone offspring

HER2 as a Therapeutic Target in Head and Neck Squamous Cell Carcinoma

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