Trastuzumab-induced recruitment of Csk-homologous kinase (CHK) to ErbB2 receptor is associated with ErbB2-Y1248 phosphorylation and ErbB2 degradation to mediate cell growth inhibition

Dokmanovic, Milos; Wu, Yun; Shen, Yi; Chen, Jieqing; Hirsch, Dianne S.; Wu, Wen Jin

doi:10.4161/cbt.29171

Cited by 52 publications

(61 citation statements)

References 39 publications

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“…Negative signals downstream of ERBB2 subsequently contribute to growth inhibition of ERBB2-positive breast cancer cells. 9,10 Taken together, these studies provide evidence that trastuzumab does not function as a TKI. …”

Section: Nishant Mohan and Wen Jin Wumentioning

confidence: 89%

“…7 Gijsen and co-workers also reported that trastuzumab induced ERBB2 tyrosine phosphorylation, 8 and together with another group observed that trastuzumab treatment induced paradoxical activation of mitogenactivated protein kinase 1/3 in breast cancer cells. 8,9 In 2014, we demonstrated that trastuzumab upregulated ERBB2 tyrosine kinase activity in trastuzumab-sensitive breast cancer cells, and that this upregulated a ctivity contributed to ERBB2 phosphorylation. 9 Despite different effects on ERBB2 phosphorylation, both lapatinib and trastuzumab have the capacity to downregulate Akt activity and to inhibit growth of breast cancer cells.…”

Section: Nishant Mohan and Wen Jin Wumentioning

confidence: 94%

“…8,9 In 2014, we demonstrated that trastuzumab upregulated ERBB2 tyrosine kinase activity in trastuzumab-sensitive breast cancer cells, and that this upregulated a ctivity contributed to ERBB2 phosphorylation. 9 Despite different effects on ERBB2 phosphorylation, both lapatinib and trastuzumab have the capacity to downregulate Akt activity and to inhibit growth of breast cancer cells. Based on our data, we postulate that binding of trastuzumab to ERBB2 could induce structural changes in the ERBB2 cytoplasmic kinase domain, leading to allosteric activation of ERBB2 kinase and trans phosphoryl ation of ERBB2.…”

Section: Nishant Mohan and Wen Jin Wumentioning

confidence: 94%

“…6 Growing evidence indicates that targeting ERBB2 using trastuzumab increases ERBB2 tyrosine phosphorylation in trastuzumab-sensitive breast cancer cells. [7][8][9] Diemeier and colleagues reported that the inhibitory effect of trastuzumab on trastuzumab-sensitive breast…”

Section: Correspondencementioning

confidence: 99%

“…Based on our data, we postulate that binding of trastuzumab to ERBB2 could induce structural changes in the ERBB2 cytoplasmic kinase domain, leading to allosteric activation of ERBB2 kinase and trans phosphoryl ation of ERBB2. 9,10 Trastuzumab-induced ERBB2 phosphorylation provides docking sites for downstream signalling molecules, which are different from those induced by a ligand (such as epidermal growth factor), in that they recruit signalling molecules such as Csk-homologous kinase, a non-receptor tyrosine kinase. Negative signals downstream of ERBB2 subsequently contribute to growth inhibition of ERBB2-positive breast cancer cells.…”

Section: Nishant Mohan and Wen Jin Wumentioning

confidence: 99%

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Trastuzumab is not a tyrosine kinase inhibitor

Mohan

2015

Nat Rev Cardiol

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CORRESPONDENCEWe read with great interest the Review by Ewer, M. S. & Ewer, S. M. (Cardiotoxicity of anticancer treatments. Nat. Rev. Cardiol. 12, 547-558;2015), 1 because it is highly relevant to our research. We appreciate the thorough review of the heart disorders and the associated molecular mechanisms elicited by receptor tyrosine-protein kinase erbB-2 (ERBB2)-targeted agents in this article. However, we believe that the authors' description of trastuzumab as "the first mono clonal antibody tyrosine kinase inhibitor" is conceptually incorrect and does not reflect the current state of literature in this field.Tyrosine kinase inhibitors (TKIs), such as lapatinib, inhibit the kinase activity of epidermal growth factor receptor (EGFR), and ERBB2 and ligand-induced receptor phosphorylation by reversibly binding to the ATP-binding site of the kinase. 2 Cetuximab, a therapeutic monoclonal antibody directed against the extracellular domain of EGFR, acts as a TKI to block the activation of EGFR tyrosine kinase by competing for ligand binding. 3,4 Trastuzumab is a therapeutic monoclonal antibody directed against the extracellular domain of ERBB2. 5 However, the effects of trastuzumab on ERBB2 kinase activity are different from those of TKIs and cetuximab. An anti-ERBB2 mono clonal antibody 4D5, which was later humanized to generate trastuzumab, was shown to exhibit agonistic signalling, resulting in increased ERBB2 phosphorylation that correlated with its inhibitory effect on ERBB2-overexpressing breast cancer cells. 6 Growing evidence indicates that targeting ERBB2 using trastuzumab increases ERBB2 tyrosine phosphorylation in trastuzumab-sensitive breast cancer cells. 7-9 Diemeier and colleagues reported that the inhibitory effect of trastuzumab on trastuzumab-sensitive breast

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Section: Nishant Mohan and Wen Jin Wumentioning

confidence: 89%

Section: Nishant Mohan and Wen Jin Wumentioning

confidence: 94%

Section: Nishant Mohan and Wen Jin Wumentioning

confidence: 94%

Section: Correspondencementioning

confidence: 99%

Section: Nishant Mohan and Wen Jin Wumentioning

confidence: 99%

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Trastuzumab is not a tyrosine kinase inhibitor

Mohan

2015

Nat Rev Cardiol

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Sortilin‐related receptor is a druggable therapeutic target in breast cancer

et al. 2021

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In breast cancer, the currently approved anti-receptor tyrosine-protein kinase erbB-2 (HER2) therapies do not fully meet the expected clinical goals due to therapy resistance. Identifying alternative HER2-related therapeutic targets could offer a means to overcome these resistance mechanisms. We have previously demonstrated that an endosomal sorting protein, sortilin-related receptor (SorLA), regulates the traffic and signaling of HER2 and HER3, thus promoting resistance to HER2-targeted therapy in breast cancer. This study aims to assess the feasibility of targeting SorLA using a monoclonal antibody. Our results demonstrate that anti-SorLA antibody (SorLA ab) alters the resistance of breast cancer cells to HER2 monoclonal antibody trastuzumab in vitro and in ovo. We found that SorLA ab and trastuzumab combination therapy also inhibits tumor cell proliferation and tumor cell density in a mouse xenograft model of HER2-positive breast cancer. In addition, SorLA ab inhibits the proliferation of breast cancer patient-derived explant three-dimensional cultures. These results provide, for the first time, proof of principle that SorLA is a druggable target in breast cancer.

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Engineering antibodies with cancer‐associated binding sites

Tian,

Pan,

Zhang

et al. 2024

BMEMat

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Cancer immunotherapy has appeared as a prospective therapeutic modality. Therapeutic antibodies induced in an in vitro expression system act as “targeting missiles” against tumor‐associated binding sites, and subsequently, immune system attack on tumors is restored or boosted. These antibody regimens are engineered towards enhanced Fc efficacy, humanization, and fragmentation to specifically recognize and bind to effective tumor‐associated targets. The challenge lies in obtaining efficient therapeutic regimens with low response rates, acquisition of resistance, and immune‐related undesirable effects of artificially designed therapeutic antibodies, which is crucial for enhancing clinical efficacy. This review provides an in‐depth introduction to antibodies that perform direct/indirect roles in cancer treatment by binding to immune checkpoints, co‐stimulatory receptors, and extracellular membrane receptors. It also discusses how antibodies kill tumors and modulate microenvironment of tumor through these targets. The classification of expression systems for antibody production is summarized to guide appropriate selection based on different specificities. Understanding antibody sources, ongoing evaluation of engineered antibodies, and tumor‐associated antigen research pave the way for designing appropriate antibody‐based immunotherapy regimens.

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Trastuzumab-induced recruitment of Csk-homologous kinase (CHK) to ErbB2 receptor is associated with ErbB2-Y1248 phosphorylation and ErbB2 degradation to mediate cell growth inhibition

Cited by 52 publications

References 39 publications

Trastuzumab is not a tyrosine kinase inhibitor

Trastuzumab is not a tyrosine kinase inhibitor

Sortilin‐related receptor is a druggable therapeutic target in breast cancer

Engineering antibodies with cancer‐associated binding sites

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