Mechanisms Underlying the Action and Synergism of Trastuzumab and Pertuzumab in Targeting HER2-Positive Breast Cancer

Nami, Babak; Maadi, Hamid; Wang, Zhixiang

doi:10.3390/cancers10100342

Cited by 135 publications

(112 citation statements)

References 184 publications

(279 reference statements)

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“…HER2 overexpression results in overactivation of downstream PI3K/Akt, PLC-ɣ and MAPK pathways leading to increased tumor cell growth, survival, motility, and invasion [10]. Targeting HER2 by small molecule inhibitors and monoclonal antibodies is the current therapy for HER2-positive breast cancer that outcome significant tumor regression in the patients [11,12]. Lapatinib, a small molecule dual inhibitor of tyrosine kinase activity of HER2 and EGFR, and trastuzumab (Herceptin) and pertuzumab (Perjeta) which are anti-HER2 humanized monoclonal antibodies targeting ECD of HER2 approved by FDA to treat patients with early-stage and metastatic HER2-positive breast cancer as an adjuvant in combination with taxane therapy [11,13,14].…”

Section: Introductionmentioning

confidence: 99%

“…Unfortunately, development of acquired resistance to HER2-targeted therapies continues as a big obstacle in the treatment of HER2-positive breast cancer. Approximately 60-70% of HER2positive breast cancer patients develop de novo resistance to trastuzumab, partially due to the loss of HER2 expression on their tumor cells during the treatment [11,12,15]. A suggested mechanism of trastuzumab resistance is cleavage and shedding of HER2.…”

Section: Introductionmentioning

confidence: 99%

“…Cleavage from EJM region will result in shedding of the extracellular part of HER2 and production of p95HER2 still encored at the plasma membrane. While, in the case of cleavage from IJM region, the intracellular part of HER2 will shed and the extracellular part will remain at the plasma membrane [11,12,16,17]. Both cleavage cases that can take place by proteinases during epithelial-mesenchymal transition (EMT) of HER2-positive breast cancer, that leads to emergence of tumor cells resistant to trastuzumab but still sensitive to lapatinib [12].…”

Section: Introductionmentioning

confidence: 99%

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Epigenetic downregulation of HER2 during EMT leads to tumor resistance to HER2-targeted therapies in breast cancer

Nami

Wang

2020

Preprint

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HER2 receptor tyrosine kinase (encoded by ERBB2 gene) is overexpressed in approximately 25% of all breast cancer tumors (known as HER2-positive breast cancers). Overexpression of HER2 causes overactivation of downstream receptor tyrosine kinase pathways including PI3K/Akt and MAPK pathways and is a poor prognosis factor in breast cancer. Tyrosine kinase inhibitor lapatinib and anti-HER2 monoclonal antibodies trastuzumab and pertuzumab are FDA-approved HER2-targeted drugs for treatment of HER2-positive breast cancers. However, development of de novo resistance to HER2 blockade occurs in majority of patients after treatment started. Resistance to HER2 targeting therapies partially due to the loss of HER2 expression on their tumor cells during the treatment. But little is known about the exact mechanism of loss of HER2 on originally HER2-positive tumor cells. Downregulation of extracellular HER2 by metalloproteinases during epithelial-mesenchymal transition (EMT) in trastuzumabresistant/lapatinib-sensitive cells has been shown by limited studies, however, the mechanism of ERBB2 gene silencing during EMT and in the mesenchymal-like cells derived from trastuzumab-resistant/lapatinibresistant HER2-positive breast tumors was entirely unknown. In this study, hypothesized that EMT abrogates HER2 expression by chromatin-based epigenetic silencing of ERBB2 gene as a mechanism of acquired resistance to HER2-targeted therapies. we found that HER2 expression is positively and negatively correlated with the expression of epithelial and mesenchymal phenotype marker genes respectively in breast cancer tumors. We also found that chromatin of ERBB2 gene in HER2-high epithelial-like breast cancer cells is active, while, the chromatin is inactive in HER2-low mesenchymal-like cells. HER2-low breast cancer cell line also revealed less promoter-enhancer interaction and small chromatin loops compared to the HER2-high cell lines. The lower HER2 expression, the higher EMT phenotype, and inactivated chromatin all were found correlated with a lower response to lapatinib. The higher EMT phenotype was found correlated with a lower response to lapatinib. We also found that induction of EMT of HER2-positive breast cancer BT474 cells results in downregulated HER2 expression and lower binding rate of trastuzumab to the cells. These results show that the downregulation of HER2 in mesenchymal-like cells in the culture of HER2-positive breast cancer cell lines was due to ERBB2 gene silencing by epigenetic reprogramming of the cells during EMT. These results indicate that ERBB2 gene silencing by epigenetic regulation during EMT is the main mechanism of resistance of HER2-positive breast cancer cells to trastuzumab and lapatinib.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Epigenetic downregulation of HER2 during EMT leads to tumor resistance to HER2-targeted therapies in breast cancer

Nami

Wang

2020

Preprint

Self Cite

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“…The effective response of mAbs in different cancer types have also been well documented [139]. Trastuzumab (Herceptin) targets the ectodomain domain of the ErbB family member (ERBB2) and is the first to be clinically approved [140], it has demonstrated good anti-tumor potential [141]. Pertuzumab is reported to have an effective response in various types of cancer [136].…”

Section: Equating Antibodies and Small-molecule Therapies In Cancer Tmentioning

confidence: 99%

“…Pertuzumab is reported to have an effective response in various types of cancer [136]. The ERBB2-targeted therapeutics, trastuzumab, and Pertuzumab employ signal blockade involving inhibition of ligand interactions, receptor downregulation and interference with receptor dimerization to bring about their therapeutic responses [141].…”

Section: Equating Antibodies and Small-molecule Therapies In Cancer Tmentioning

confidence: 99%

Exploring receptor tyrosine kinases-inhibitors in Cancer treatments

Metibemu

Akinloye

Akamo

et al. 2019

Egypt J Med Hum Genet

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Background: Receptor tyrosine kinases (RTKs) are signaling enzymes responsible for the transfer of Adenosine triphosphate (ATP) γ-phosphate to the tyrosine residues substrates. RTKs demonstrate essential roles in cellular growth, metabolism, differentiation, and motility. Anomalous expression of RTK customarily leads to cell growth dysfunction, which is connected to tumor takeover, angiogenesis, and metastasis. Understanding the structure, mechanisms of adaptive and acquired resistance, optimizing inhibition of RTKs, and eradicating cum minimizing the havocs of quiescence cancer cells is paramount. MainText: Tyrosine kinase inhibitors (TKIs) vie with RTKs ATP-binding site for ATP and hitherto reduce tyrosine kinase phosphorylation, thus hampering the growth of cancer cells. TKIs can either be monoclonal antibodies that compete for the receptor's extracellular domain or small molecules that inhibit the tyrosine kinase domain and prevent conformational changes that activate RTKs. Progression of cancer is related to aberrant activation of RTKs due to due to mutation, excessive expression, or autocrine stimulation. Conclusions:Understanding the modes of inhibition and structures of RTKs is germane to the design of novel and potent TKIs. This review shed light on the structures of tyrosine kinases, receptor tyrosine kinases, tyrosine kinase inhibitors, minimizing imatinib associated toxicities, optimization of tyrosine kinase inhibition in curtailing quiescence in cancer cells and the prospects of receptor tyrosine kinase based treatments.

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Top advances of the year: Precision oncology

Desai

Reddy

Subbiah

2023

Cancer

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The advent of precision medicine has changed the landscape of oncologic biomarkers, drug discovery, drug development, and, more importantly, outcomes for patients with cancer. Precision oncology entails the genomic profiling of tumors to detect actionable aberrations. The advances in clinical next-generation sequencing from both tumor tissue and liquid biopsy and availability of targeted therapies has rapidly entered mainstream clinical practice. In this review, recent major developments in precision oncology that have affected outcomes for patients with cancer are discussed. Rapid clinical development was seen of targeted agents across various mutational profiles such as KRASG12C (which was considered "undruggable" for almost 4 decades), Exon 20 insertions, and RET mutations. Approaches to precision chemotherapy delivery by the introduction of antibody drug conjugates in the armamentarium against lung cancer has been appreciated. K E Y W O R D Santibody drug conjugates, cancer, oncogenic driver, precision oncology, targeted therapy Lung cancer is one of the most aggressive tumor types, with 131,880 estimated deaths from this disease in 2021. 1 Targeted therapies stratified by oncogenic drivers have substantially improved therapeutic outcomes in patients with non-small cell lung cancer (NSCLC). 2 However, such oncogenic drivers are not found in 25% to 40% of cases of lung adenocarcinoma. Identifying new therapeutic targets is imperative to improve outcomes in NSCLC 3 (Table 1). Izumi et al. recently reported a novel fusion transcript ofCLIP1 and LTK using whole-transcriptome sequencing in a multiinstitutional genome screening platform. 4 The CLIP1-LTK fusion was present in 0.4% of NSCLCs and was mutually exclusive to other known oncogenic drivers. The authors demonstrated that kinase activity of the CLIP1-LTK fusion protein is constitutively activated and that it has transformation potential. Furthermore, there was preclinical evidence of inhibition of CLIP1-LTK kinase with lorlatinib with good clinical response in an n-of-1 study. This novel fusion target may be another target for routine screening. Clinical development of therapeutic agents for this new oncogenic driver is now warranted. KRAS G12CActivating mutations in Kirsten rat sarcoma viral oncogene homologue (KRAS) are found in 25% to 30% of nonsquamous cell NSCLCs, representing the most prevalent genomic driver event in NSCLC. 5 Aakash Desai and Neha K. Reddy contributed equally.

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Mechanisms Underlying the Action and Synergism of Trastuzumab and Pertuzumab in Targeting HER2-Positive Breast Cancer

Cited by 135 publications

References 184 publications

Epigenetic downregulation of HER2 during EMT leads to tumor resistance to HER2-targeted therapies in breast cancer

Epigenetic downregulation of HER2 during EMT leads to tumor resistance to HER2-targeted therapies in breast cancer

Exploring receptor tyrosine kinases-inhibitors in Cancer treatments

Top advances of the year: Precision oncology

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