Epigenetic Silencing of HER2 Expression during Epithelial-Mesenchymal Transition Leads to Trastuzumab Resistance in Breast Cancer

Nami, Babak; Black, Corbin; Wang, Zhixiang

doi:10.3390/life11090868

Cited by 10 publications

(6 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Previously, we and others reported that long-term exposure to MPE/MA led to epithelial-mesenchymal transition (EMT), antigen loss, as well as treatment resistance. 16 , 31 To exclude the potential influence of continuous exposure to MPE/MA, such as HER2 antigen loss, we cultured SKOV3 PD-L1 cells in MA-supernatant from an OSC patient (Pt4) for 1 month (MA-treated SKOV3 PD-L1 ), and found that the levels of HER2 and PD-L1 expressions were similar on MA-treated and untreated SKOV3 PD-L1 cells (Fig. 2c and Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

A PD-L1-targeting chimeric switch receptor enhances efficacy of CAR-T cell for pleural and peritoneal metastasis

Zhang

et al. 2022

Sig Transduct Target Ther

View full text Add to dashboard Cite

Pleural and peritoneal metastasis accompanied by malignant pleural effusion (MPE) or malignant ascites (MA) is frequent in patients with advanced solid tumors that originate from the lung, breast, gastrointestinal tract and ovary. Regional delivery of CAR-T cells represents a new strategy to control tumor dissemination in serous cavities. However, malignant effusions constitute an immune-suppressive environment that potentially induces CAR-T cell dysfunction. Here, we demonstrated that the anti-tumor cytotoxicity of conventional 2nd-generation CAR-T cells was significantly inhibited by both the cellular and non-cellular components of MPE/MA, which was primarily attributed to impaired CAR-T cell proliferation and cytokine production in MPE/MA environment. Interestingly, we found that PD-L1 was widely expressed on freshly-isolated MPE/MA cells. Based on this feature, a novel PD-L1-targeting chimeric switch receptor (PD-L1.BB CSR) was designed, which can bind to PD-L1, switching the inhibitory signal into an additional 4-1BB signal. When co-expressed with a 2nd-generation CAR, PD-L1.BB CSR-modified CAR-T cells displayed superior fitness and enhanced functions in both culture medium and MPE/MA environment, causing rapid and durable eradication of pleural and peritoneal metastatic tumors in xenograft models. Further investigations revealed elevated expressions of T-cell activation, proliferation, and cytotoxicity-related genes, and we confirmed that PD-L1 scFv and 4-1BB intracellular domain, the two important components of PD-L1.BB CSR, were both necessary for the functional improvements of CAR-T cells. Overall, our study shed light on the clinical application of PD-L1.BB CSR-modified dual-targeting CAR-T cells. Based on this study, a phase I clinical trial was initiated in patients with pleural or peritoneal metastasis (NCT04684459).

show abstract

Section: Resultsmentioning

confidence: 99%

A PD-L1-targeting chimeric switch receptor enhances efficacy of CAR-T cell for pleural and peritoneal metastasis

Zhang

et al. 2022

Sig Transduct Target Ther

View full text Add to dashboard Cite

show abstract

“…In this study, the H3K9ac and H3K27me3 epigenetic profiles and microanalysis of genes enriched with the promoter h3k9ac chip revealed epi-promoter regions of genes modified by mark at HER2+ and TNBC tumors. The H3K9ac modification has been reported to induce downregulation of most of the related genes in HER2-amplified tumors [74]. Descriptive investigations of the HER2/neu epigenetics in BC support the repression of Her2/neu by increased H3K9me2.…”

Section: Her2(+) Breast Cancermentioning

confidence: 94%

Molecular Mechanisms of Breast Cancer Metastasis

Yurekli¹,

Abay²,

Tutar³

et al. 2023

Cancer Metastasis - Molecular Mechanism and Clinical Therapy

View full text Add to dashboard Cite

Breast cancer (BC) is one of the most frequently occurring diseases with high morbidity and mortality rates in the world today. BC cells live under stress with altered pathway signaling, chromosome and microsatellite instability, aneuploidy, hypoxia, low pH, and low nutrient conditions. In order to survive and reproduce in these stressful environments, BC cells rapidly undergo adaptive mutations, rearrange their chromosomes, and repress tumor suppressor genes while inducing oncogene activities that cause the natural selection of cancer cells and result in heterogeneous cancer cells in the tumor environment. Unfortunately, these genetic alterations result in aggressive BC cells that can not only proliferate aggressively but also migrate and invade the other tissues in the body to form secondary tumors. In this review, molecular mechanisms of metastasis of BC subtypes are discussed.

show abstract

“…Studies have shown that approximately 60% to 70% of patients with HER2‐positive BC develop resistance to trastuzumab due to the cleavage and shedding of HER2. The induction of epithelial‐mesenchymal transition (EMT) in HER2‐overexpressing epithelioid BC cells can lead to the down‐regulation of HER2 expression through the epigenetic silencing of ERBB2 gene in chromatin, forming a “HER2 negative” subtype, thereby reducing the binding rate of trastuzumab to cells and leading to the resistance of trastuzumab 79 . Therefore, the prognosis and drug tolerance of HER2 positive and negative patients may be improved by EMTs in the future.…”

Section: Treatment Of Her2‐low/zero Breast Cancermentioning

confidence: 99%

The trichotomy of HER2 expression confers new insights into the understanding and managing for breast cancer stratified by HER2 status

Jiang

Liu

et al. 2023

Intl Journal of Cancer

View full text Add to dashboard Cite

Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase receptor that plays a carcinogenic role in breast cancer (BC) through gene amplification, mutation, or overexpression. Traditional methods of HER2 detection were divided into positive (immunohistochemistry (IHC) 3+/fluorescence in situ hybridization (FISH) amplification) and negative (IHC 2+/FISH−, IHC 1+, IHC 0) according to the dichotomy method. Anti‐HER2‐targeted therapies, such as trastuzumab and pertuzumab, have significantly improved the prognosis of HER2‐positive patients. However, up to 75% to 85% of patients remain HER2‐negative. In recent years, with the rapid development of molecular biology, gene detection technology, targeted therapy, and immunotherapy, researchers have actively explored the clinicopathological characteristics, molecular biological characteristics, treatment methods, and HER2 detection methods of HER2‐low/zero breast cancer. With the clinical efficacy of new anti‐HER2 targeted drugs, accurate classification of breast cancer is very important for the treatment choice. Therefore, the following review summarizes the necessity of developing HER2 detection methods, and the clinicopathological and drug treatment characteristics of patients with HER2‐low/zero, to light the dawn of the treatment of breast cancer patients with HER2‐low/zero expression.

show abstract

Epigenetic Silencing of HER2 Expression during Epithelial-Mesenchymal Transition Leads to Trastuzumab Resistance in Breast Cancer

Cited by 10 publications

References 46 publications

A PD-L1-targeting chimeric switch receptor enhances efficacy of CAR-T cell for pleural and peritoneal metastasis

A PD-L1-targeting chimeric switch receptor enhances efficacy of CAR-T cell for pleural and peritoneal metastasis

Molecular Mechanisms of Breast Cancer Metastasis

The trichotomy of HER2 expression confers new insights into the understanding and managing for breast cancer stratified by HER2 status

Contact Info

Product

Resources

About