Dataset Information

Melatonin potentiates the cytotoxic effect of Neratinib in HER2⁺ breast cancer through promoting endocytosis and lysosomal degradation of HER2.

ABSTRACT: Complete blockade of the HER2 protein itself and HER signaling network is critical to achieving effective HER2-targeted therapies. Despite the success of HER2-targeted therapies, the diseases will relapse in a significant fraction of patients with HER2⁺ breast cancers. How to improve the therapeutic efficacy of existing HER2-targeted agents remains an unmet clinical need. Here, we uncover a role of Melatonin in diminishing HER2-mediated signaling by destruction of HER2 protein. Mechanistically, Melatonin treatment attenuated the protective effect of the HSP90 chaperone complex on its client protein HER2, triggering ubiquitylation and subsequent endocytic lysosomal degradation of HER2. The inhibitory effect of Melatonin on HER2 signaling substantially enhanced the cytotoxic effects of the pan-HER inhibitor Neratinib in HER2⁺ breast cancer cells. Lastly, we demonstrate that dual inhibition of HER2 by combined use of Melatonin and Neratinib effectively blocked the growth of HER2⁺ breast tumor xenografts in vivo. Our findings shed light on the potential use of Melatonin in a novel dual HER2 blockade strategy for HER2⁺ breast cancer treatment.

SUBMITTER: Liu Z

PROVIDER: S-EPMC8566236 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Melatonin potentiates the cytotoxic effect of Neratinib in HER2<sup>+</sup> breast cancer through promoting endocytosis and lysosomal degradation of HER2.

Liu Zundong Z Sang Xiaolin X Wang Min M Liu Yichao Y Liu Jiao J Wang Xuefei X Liu Pixu P Cheng Hailing H

Oncogene 20210923 44

Complete blockade of the HER2 protein itself and HER signaling network is critical to achieving effective HER2-targeted therapies. Despite the success of HER2-targeted therapies, the diseases will relapse in a significant fraction of patients with HER2<sup>+</sup> breast cancers. How to improve the therapeutic efficacy of existing HER2-targeted agents remains an unmet clinical need. Here, we uncover a role of Melatonin in diminishing HER2-mediated signaling by destruction of HER2 protein. Mechan ...[more]

PMID: 34556812

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Project description:BackgroundHuman epidermal growth factor receptor-2 (HER2)-targeted therapies prolong survival in HER2-positive breast cancer patients. Benefit stems primarily from improved control of systemic disease, but up to 50% of patients progress to incurable brain metastases due to acquired resistance and/or limited permeability of inhibitors across the blood-brain barrier. Neratinib, a potent irreversible pan-tyrosine kinase inhibitor, prolongs disease-free survival in the extended adjuvant setting, and several trials evaluating its efficacy alone or combination with other inhibitors in early and advanced HER2-positive breast cancer patients are ongoing. However, its efficacy as a first-line therapy against HER2-positive breast cancer brain metastasis has not been fully explored, in part due to the lack of relevant pre-clinical models that faithfully recapitulate this disease. Here, we describe the development and characterisation of a novel syngeneic model of spontaneous HER2-positive breast cancer brain metastasis (TBCP-1) and its use to evaluate the efficacy and mechanism of action of neratinib.MethodsTBCP-1 cells were derived from a spontaneous BALB/C mouse mammary tumour and characterised for hormone receptors and HER2 expression by flow cytometry, immunoblotting and immunohistochemistry. Neratinib was evaluated in vitro and in vivo in the metastatic and neoadjuvant setting. Its mechanism of action was examined by transcriptomic profiling, function inhibition assays and immunoblotting.ResultsTBCP-1 cells naturally express high levels of HER2 but lack expression of hormone receptors. TBCP-1 tumours maintain a HER2-positive phenotype in vivo and give rise to a high incidence of spontaneous and experimental metastases in the brain and other organs. Cell proliferation/viability in vitro is inhibited by neratinib and by other HER2 inhibitors, but not by anti-oestrogens, indicating phenotypic and functional similarities to human HER2-positive breast cancer. Mechanistically, neratinib promotes a non-apoptotic form of cell death termed ferroptosis. Importantly, metastasis assays demonstrate that neratinib potently inhibits tumour growth and metastasis, including to the brain, and prolongs survival, particularly when used as a neoadjuvant therapy.ConclusionsThe TBCP-1 model recapitulates the spontaneous spread of HER2-positive breast cancer to the brain seen in patients and provides a unique tool to identify novel therapeutics and biomarkers. Neratinib-induced ferroptosis provides new opportunities for therapeutic intervention. Further evaluation of neratinib neoadjuvant therapy is warranted.

Dataset Information

Melatonin potentiates the cytotoxic effect of Neratinib in HER2⁺ breast cancer through promoting endocytosis and lysosomal degradation of HER2.

Publications

Melatonin potentiates the cytotoxic effect of Neratinib in HER2<sup>+</sup> breast cancer through promoting endocytosis and lysosomal degradation of HER2.

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Dataset Information

Melatonin potentiates the cytotoxic effect of Neratinib in HER2+ breast cancer through promoting endocytosis and lysosomal degradation of HER2.

Publications

Melatonin potentiates the cytotoxic effect of Neratinib in HER2<sup>+</sup> breast cancer through promoting endocytosis and lysosomal degradation of HER2.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Melatonin potentiates the cytotoxic effect of Neratinib in HER2⁺ breast cancer through promoting endocytosis and lysosomal degradation of HER2.