The Changing Paradigm for the Treatment of HER2-Positive Breast Cancer

Patel, Aena; Unni, Nisha; Peng, Yan

doi:10.3390/cancers12082081

Cited by 103 publications

(76 citation statements)

References 69 publications

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“…Similar, triple inhibition of EGFR, HER2 and HER4 via the pan-HER inhibitor neratinib was shown to be superior over lapatinib in a phase III trial for brain metastatic breast cancer [67]. In fact, second line therapy approaches and ongoing trials for (neo)adjuvant and advanced metastatic breast cancer combine chemotherapy with either trastuzumab and pertuzumab or T-DM1, or trastuzumab with small compound inhibitors like lapatinib, gefitinib or neratinib [67][68][69][70][71][72]. Thus, these second line therapeutic approaches tackle heterodimer formation or aim to block receptor activation by mono-, duo-or pan-specific EGFR and or HER inhibitors.…”

Section: Discussionmentioning

confidence: 99%

EGFR Expression in HER2-Driven Breast Cancer Cells

Weinberg

Peckys

Jonge

2020

IJMS

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The epidermal growth factor receptor HER2 is overexpressed in 20% of breast cancer cases. HER2 is an orphan receptor that is activated ligand-independently by homodimerization. In addition, HER2 is able to heterodimerize with EGFR, HER3, and HER4. Heterodimerization has been proposed as a mechanism of resistance to therapy for HER2 overexpressing breast cancer. Here, a method is presented for the simultaneous detection of individual EGFR and HER2 receptors in the plasma membrane of breast cancer cells via specific labeling with quantum dot nanoparticles (QDs). Correlative fluorescence microscopy and liquid phase electron microscopy were used to analyze the plasma membrane expression levels of both receptors in individual intact cells. Fluorescent single-cell analysis of SKBR3 breast cancer cells dual-labeled for EGFR and HER2 revealed a heterogeneous expression for receptors within both the cell population as well as within individual cells. Subsequent electron microscopy of individual cells allowed the determination of individual receptors label distributions. QD-labeled EGFR was observed with a surface density of (0.5–5) × 101 QDs/µm2, whereas labeled HER2 expression was higher ranging from (2–10) × 102 QDs/µm2. Although most SKBR3 cells expressed low levels of EGFR, an enrichment was observed at large plasma membrane protrusions, and amongst a newly discovered cellular subpopulation termed EGFR-enriched cells.

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Section: Discussionmentioning

confidence: 99%

EGFR Expression in HER2-Driven Breast Cancer Cells

Weinberg

Peckys

Jonge

2020

IJMS

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“…Trastuzumab and lapatinib are the major anti-HER2 therapeutic reagents for HER2+ breast cancer (5). Since blocking Gi/o-GPCR signaling suppressed HER2-induced tumor growth, we further tested if targeting Gi/o-GPCRs affects the therapeutic efficacy of trastuzumab and lapatinib in Neu, MCF10A/HER2, BT474, and BT474R cells.…”

Section: Targeting Gi/o-gpcr Signaling By Ptx Enhances the Her2-targeted Therapymentioning

confidence: 99%

“…The most successful treatment for HER2 + breast cancer is HER2-targeted therapy (5). Several Food and Drug Administration (FDA)-approved anti-HER2 drugs, including the humanized monoclonal antibody, trastuzumab, and the small-molecule dual inhibitor of HER2 and EGFR, lapatinib, significantly improved clinical outcomes of patients with HER2 + breast cancer.…”

Section: Introductionmentioning

confidence: 99%

“…Several Food and Drug Administration (FDA)-approved anti-HER2 drugs, including the humanized monoclonal antibody, trastuzumab, and the small-molecule dual inhibitor of HER2 and EGFR, lapatinib, significantly improved clinical outcomes of patients with HER2 + breast cancer. Nevertheless, tumors that initially respond to HER2targeted therapy can eventually develop resistance (5). Thus, to improve clinical outcomes of advanced HER2 + breast cancer, it is critical to develop novel therapeutic approaches that can improve efficacy of HER2-targeted therapy.…”

Section: Introductionmentioning

confidence: 99%

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Targeting G_i/o protein-coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy

Lyu

Lensing

et al. 2021

Preprint

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G protein coupled receptors (GPCRs) are among the most desirable drug targets for human disease. Although GPCR dysfunction drives the development and progression of many tumors including breast cancer (BC), targeting individual GPCRs has limited efficacy as a cancer therapy because numerous GPCRs are activated. In this study, we sought a new way of blocking GPCR activation in HER2+-BC by targeting a subgroup of GPCRs that couple to Gi/o proteins (Gi/o-GPCRs). Using cell lines and transgenic mouse models, we showed in mammary epithelial cells, HER2 hyperactivation altered GPCR expression, particularly, Gi/o-GPCRs. Gi/o-GPCR stimulation transactivated EGFR and HER2, which in turn activated the PI3K/AKT and Src pathways. Uncoupling Gi/o-GPCRs from cognate Gi/o proteins by pertussis toxin (PTx) inhibited BC cell proliferation and migration in vitro and suppressed HER2-driven tumor formation and metastasis in vivo. Moreover, targeting Gi/o-GPCR signaling via PTx, PI3K, or Src inhibitors enhanced HER2-targeted therapy. These results indicate that HER2 hyperactivation in BC cells drives aberrant Gi/o-GPCR signaling, and Gi/o-GPCR signals converge on PI3K/AKT and Src signaling pathways to promote cancer progression and the development of resistance to HER2-targeted therapy. Our findings suggest a new way to pharmacologically deactivate GPCR signaling to block tumor growth and enhance therapeutic efficacy.

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“…The human epidermal growth factor receptor family member HER2 (ErbB2) is an established target structure in cancer therapy. 1 HER2 is highly overexpressed in ~20% of primary invasive breast cancers, and HER2 aberrations were also identified in gastric cancer, as well as biliary tract, colorectal, non-small-cell lung and bladder cancers. 2–4 Activation of the epidermal growth factor receptor (EGFR) family members by dimerization can lead to several cellular responses involved in tumor formation and progression.…”

Section: Introductionmentioning

confidence: 99%

A bivalent, bispecific Dab-Fc antibody molecule for dual targeting of HER2 and HER3

Rau

Kocher

Rommel

et al. 2021

mAbs

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Dual targeting of surface receptors with bispecific antibodies is attracting increasing interest in cancer therapy. Here, we present a novel bivalent and bispecific antagonistic molecule (Dab-Fc) targeting human epidermal growth factors 2 and 3 (HER2 and HER3) derived from the Db-Ig platform, which was developed for the generation of multivalent and multispecific antibody molecules. Dab-Fc comprises the variable domains of the anti-HER2 antibody trastuzumab and the anti-HER3 antibody 3–43 assembled into a diabody-like structure stabilized by C H 1 and C L domains and further fused to a human γ1 Fc region. The resulting Dab-Fc 2 × 3 molecule retained unhindered binding to both antigens and was able to bind both antigens sequentially. In cellular experiments, the Dab-Fc 2 × 3 molecule strongly bound to different tumor cell lines expressing HER2 and HER3 and was efficiently internalized. This was associated with potent inhibition of the proliferation and migration of these tumor cell lines. Furthermore, IgG-like pharmacokinetics and anti-tumoral activity were demonstrated in a xenograft tumor model of the gastric cancer cell-line NCI-N87. These results illustrate the suitability of our versatile Db-Ig platform technology for the generation of bivalent bispecific molecules, which has been successfully used here for the dual targeting of HER2 and HER3.

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The Changing Paradigm for the Treatment of HER2-Positive Breast Cancer

Cited by 103 publications

References 69 publications

EGFR Expression in HER2-Driven Breast Cancer Cells

EGFR Expression in HER2-Driven Breast Cancer Cells

Targeting G_i/o protein-coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy

A bivalent, bispecific Dab-Fc antibody molecule for dual targeting of HER2 and HER3

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The Changing Paradigm for the Treatment of HER2-Positive Breast Cancer

Cited by 103 publications

References 69 publications

EGFR Expression in HER2-Driven Breast Cancer Cells

EGFR Expression in HER2-Driven Breast Cancer Cells

Targeting Gi/o protein-coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy

A bivalent, bispecific Dab-Fc antibody molecule for dual targeting of HER2 and HER3

Contact Info

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Targeting G_i/o protein-coupled receptor signaling blocks HER2-induced breast cancer development and enhances HER2-targeted therapy