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Targeting the Human Epidermal Growth Factor Receptor Family in Breast Cancer beyond HER2.

ABSTRACT: Currently, the dichotomous definition of human epidermal growth factor receptor 2 (HER2)-positive versus HER2-negative disease undergoing a change through inclusion of the identification of the "HER2-low" category, for which new therapeutic compounds in the form of potent antibody drug conjugates (ADC) may be effective. In addition, resistance to HER2-directed targets has become a clinical challenge and, therefore, strategies to bypass the HER2 receptor are of high interest. These are new HER2 ADCs and tyrosine kinase inhibitors, such as tucatinib or neratinib. The underlying mechanisms of resistance to anti-HER2 therapies and compensatory pathways are complex and a wide range of mechanisms of resistance may coexist in the same cell. Therefore, the combined treatment with agents that interact with HER2-associated downstream signaling pathways like the phosphoinositide-3-kinase (PI3K) and the serine/threonine kinases AKT and mTOR might overcome HER2 resistance. In addition, targeting other members of the HER family is a promising approach to improve outcomes in breast cancer patients. This review gives an overview of treatment strategies in targeting HER2 and other members of the HER family, not only in HER2-positive breast cancer, but also in HER2-low expressing tumors, and of approaches to overcome HER2 resistance.

SUBMITTER: Riecke K

PROVIDER: S-EPMC7768135 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Oesophageal squamous cell carcinomas and oesophageal adenocarcinomas show distinct patterns of ErbB expression and dimers. The functional effects of specific ErbB homodimers or heterodimers on oesophageal (cancer) cell behaviour, particularly invasion during early carcinogenesis, remain unknown. Here, a new cellular model system for controlled activation of epidermal growth factor receptor (EGFR) or human epidermal growth factor receptor 2 (HER2) and EGFR-HER2 or HER2-human epidermal growth factor receptor 3 (HER3) homodimers and heterodimers was studied in non-neoplastic squamous oesophageal epithelial Het-1A cells. EGFR, HER2 and HER3 intracellular domains (ICDs) were fused to dimerization domains (DmrA/DmrA and DmrC), and transduced into Het-1A cells lacking ErbB expression. Dimerization of EGFR, HER2 or EGFR-HER2 and HER2-HER3 ICDs was induced by synthetic ligands (A/A or A/C dimerizers). This was accompanied by phosphorylation of the respective EGFR, HER2 and HER3 ICDs and activation of distinct downstream signalling pathways, such as phospholipase C?1, Akt, STAT and Src family kinases. Phenotypically, ErbB dimers caused cell rounding and non-apoptotic blebbing, specifically in EGFR-HER2 and HER2-HER3 heterodimer cells. In a Transwell assay, cell migration velocity was elevated in HER2 dimer cells as compared with empty vector cells. In addition, HER2 dimer cells showed in increased cell invasion, reaching significance for induced HER2-HER3 heterodimers (P?=?0.015). Importantly, in three-dimensional organotypic cultures, empty vector cells grew as a superficial cell layer, resembling oesophageal squamous epithelium. In contrast, induced HER2 homodimer cells were highly invasive into the matrix and formed cell clusters. This was associated with partial loss of cytokeratin 7 (when HER2 homodimers were modelled) and p63 (when EGFR-HER2 heterodimers were modelled), which suggests a change or loss of squamous cell differentiation. Controlled activation of specific EGFR, HER2 and HER3 homodimers and heterodimers caused oesophageal squamous epithelial cell migration and/or invasion, especially in a three-dimensional microenvironment, thereby functionally identifying ErbB homodimers and heterodimers as important drivers of oesophageal carcinogenesis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Targeting the Human Epidermal Growth Factor Receptor Family in Breast Cancer beyond HER2.

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