Recombinant Human Erythropoietin Antagonizes Trastuzumab Treatment of Breast Cancer Cells via Jak2-Mediated Src Activation and PTEN Inactivation

Liang, Ke; Esteva, Francisco J.; Albarracin, Constance T.; Stemke-Hale, Katherine; Lü, Yang; Bianchini, Giampaolo; Yang, Ching Yi; Li, Yong; Li, Xinqun; Chen, Chun‐Te; Mills, Gordon B.; Hortobágyi, Gabriel N.; Mendelsohn, John; Hung, Mien‐Chie; Fan, Zhen

doi:10.1016/j.ccr.2010.10.025

Cited by 126 publications

(141 citation statements)

References 35 publications

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“…S6A). This result is consistent with findings from recent studies reporting that Jak2 directly phosphorylates Src and impacts the behavior of cancer cells (49,50). Importantly, we further demonstrated that the AhR protein adaptor is essential for Jak2-Src interaction in NSCLC.…”

Section: Discussionsupporting

confidence: 82%

Activation of the Aryl Hydrocarbon Receptor Leads to Resistance to EGFR TKIs in Non–Small Cell Lung Cancer by Activating Src-mediated Bypass Signaling

Zhang

Gao

et al. 2018

Clinical Cancer Research

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Purpose: The aryl hydrocarbon receptor (AhR) has been generally recognized as a ligand-activated transcriptional factor that responds to xenobiotic chemicals. Recent studies have suggested that the expression of AhR varies widely across different cancer types and cancer cell lines, but its significance in cancer treatment has yet to be clarified. Experimental Design: AhR expression in non–small cell lung cancer (NSCLC) was determined by Western blotting and IHC staining. In vitro and in vivo functional experiments were performed to determine the effect of AhR on sensitivity to targeted therapeutics. A panel of biochemical assays was used to elucidate the underlying mechanisms. Results: A high AhR protein level indicated an unfavorable prognosis for lung adenocarcinoma. Inhibition of AhR signaling sensitized EGFR tyrosine kinase inhibitors (TKIs) in NSCLC cells that express high level of endogenous AhR protein. Notably, activation of AhR by pharmacologic and molecular approaches rendered EGFR-mutant cells resistant to TKIs by restoring PI3K/Akt and MEK/Erk signaling through activation of Src. In addition, we found that AhR acts as a protein adaptor to mediate Jak2–Src interaction, which does not require the canonical transcriptional activity of AhR. Conclusions: Our results reveal a transcription-independent function of AhR and indicate that AhR may act as a protein adaptor that recruits kinases bypassing EGFR and drives resistance to TKIs. Accordingly, targeting Src would be a strategy to overcome resistance to EGFR TKIs in AhR-activated NSCLC. Clin Cancer Res; 24(5); 1227–39. ©2017 AACR.

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Section: Discussionsupporting

confidence: 82%

Activation of the Aryl Hydrocarbon Receptor Leads to Resistance to EGFR TKIs in Non–Small Cell Lung Cancer by Activating Src-mediated Bypass Signaling

Zhang

Gao

et al. 2018

Clinical Cancer Research

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“…25,26 As shown in Fig. 2A, overexpression of HER2 does not lead to a decrease but rather a moderate increase in the MFI value of HLA-ABC expression in MCF7-HER18 cells compared to MCF7 cells.…”

Section: Resultsmentioning

confidence: 96%

Trastuzumab upregulates expression of HLA-ABC and T cell costimulatory molecules through engagement of natural killer cells and stimulation of IFNγ secretion

et al. 2015

Self Cite

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It is increasingly recognized that trastuzumab, an antibody approved for treating human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer, exerts some of its antitumor effects through enhanced T cell responses. Full activation of CD8 C T cells requires both expression of major histocompatibility complex class I molecules (HLA-ABC) and expression of the T cell costimulatory molecule CD80 or CD86; however, the impact of trastuzumab treatment on the expression of HLA-ABC and CD80 and CD86 has not been investigated in HER2-overexpressing breast cancer cells. In this study, we found that, while there is no direct correlation between the expression of HER2 and HLA-ABC in breast cancer, knockdown of HER2 or inhibition of HER2 kinase by lapatinib downregulated HLA-ABC expression. Trastuzumab had no meaningful effects on HLA-ABC expression in HER2-overexpressing breast cancer cells in monoculture; however, treatment of such cells with trastuzumab in co-culture with human peripheral blood mononuclear cells (PBMC) significantly upregulated not only HLA-ABC expression but also CD86 expression. We showed that this upregulation was mediated by interferon gamma (IFNg) secreted from the natural killer (NK) cells in PBMC as a result of engagement of NK cells by trastuzumab. We further confirmed this effect of trastuzumab in vivo using a mouse mammary tumor model transduced to overexpress human HER2. Together, our data provide evidence that trastuzumab upregulates expression of HLA-ABC and T cell costimulatory molecules in HER2-overexpressing breast cancer cells in the presence of PBMC, which supports the view that T-cell-mediated immune responses are involved in trastuzumab-mediated antitumor effects.

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“…Src inhibition appears to be important to trastuzumab-mediated anti-cancer activity, as increased Src signaling is associated with trastuzumab resistance (Mitra, 2009;Liang, 2010;. One mechanism leading to increased Src activity appears to be a variant of HER2 called HER2 delta 16 (Mitra, 2009), which shows increased oncogenic activity.…”

Section: Targeting Src In Her2-overexpressing Breast Cancermentioning

confidence: 99%

“…Dual targeting of HER2Delta16 plus Src with dasatinib resulted in Src inactivation, destabilization of HER2Delta16, and decreased tumorigenicity (Mitra, 2009). In addition, Src activation via Jak2 has been shown to reduce trastuzumab activity (Liang, 2010). Recombinant human erythropoietin activated Jak2-Src signaling and inactivated PTEN in HER2-positive cells (Liang, 2010).…”

Section: Targeting Src In Her2-overexpressing Breast Cancermentioning

confidence: 99%

Novel Therapeutic Strategies and Combinations for HER2-Overexpressing Breast Cancer

Shabaya¹,

Nahta²

2011

Breast Cancer - Current and Alternative Therapeutic Modalities

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Recombinant Human Erythropoietin Antagonizes Trastuzumab Treatment of Breast Cancer Cells via Jak2-Mediated Src Activation and PTEN Inactivation

Cited by 126 publications

References 35 publications

Activation of the Aryl Hydrocarbon Receptor Leads to Resistance to EGFR TKIs in Non–Small Cell Lung Cancer by Activating Src-mediated Bypass Signaling

Activation of the Aryl Hydrocarbon Receptor Leads to Resistance to EGFR TKIs in Non–Small Cell Lung Cancer by Activating Src-mediated Bypass Signaling

Trastuzumab upregulates expression of HLA-ABC and T cell costimulatory molecules through engagement of natural killer cells and stimulation of IFNγ secretion

Novel Therapeutic Strategies and Combinations for HER2-Overexpressing Breast Cancer

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