ErbB3 Ablation Impairs PI3K/Akt-Dependent Mammary Tumorigenesis
Rebecca S. Cook,Joan T. Garrett,Violeta Sanchez,Jamie C. Stanford,Christian D. Young,Anindita Chakrabarty,Cammie Rinehart,Yixian Zhang,Yaming Wu,Lee M. Greenberger,Ivan D. Horak,Carlos L. Arteaga +11 more
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TLDR
It is reported that ErbB3 is critical for PI3K/Akt-driven tumor formation triggered by the PyVmT oncogene and EZN-3920, a chemically stabilized antisense oligonucleotide that targets the Erb B3 mRNA in vivo, produced similar effects while causing no toxicity in the mouse model.Abstract:
The ErbB receptor family member ErbB3 has been implicated in breast cancer growth but it has yet to be determined whether its disruption is therapeutically valuable. In a mouse model of mammary carcinoma driven by the polyomavirus middle T (PyVmT) oncogene, the ErbB2 tyrosine kinase inhibitor lapatinib reduced the activation of ErbB3 and Akt along with tumor cell growth. In this phosphatidylinositol-3 kinase (PI3K)-dependent tumor model, ErbB2 is part of a complex containing PyVmT, p85 (PI3K), ErbB3, and Src, that is disrupted by treatment with lapatinib. Thus, full engagement of PI3K/Akt by ErbB2 in this oncogene-induced mouse tumor model may involve its ability to dimerize with and phosphorylate ErbB3, which itself directly binds PI3K. Here we report that ErbB3 is critical for PI3K/AKT-driven tumor formation triggered by the PyVmT oncogene. Tissue-specific, Cre-mediated deletion of ErbB3 reduced Akt phosphorylation, primary tumor growth and pulmonary metastasis. Further EZN-3920, a chemically stabilized antisense oligonucleotide that targets the ErbB3 mRNA in vivo, produced similar effects while causing no mouse toxicity. Our findings offer further preclinical evidence that ErbB3 ablation may be therapeutically effective in tumors where ErbB3 engages PI3K/Akt signaling.read more
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ERBB receptors: from oncogene discovery to basic science to mechanism-based cancer therapeutics.
TL;DR: Current paradigms of targeting ERBB receptors with cancer therapeutics and the understanding of mechanisms of action and resistance to these drugs are discussed.
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MerTK inhibition in tumor leukocytes decreases tumor growth and metastasis.
Rebecca S. Cook,Kristen M. Jacobsen,Anne M. Wofford,Deborah DeRyckere,Jamie C. Stanford,Anne L. Prieto,Elizabeth F. Redente,Melissa Sandahl,Debra Hunter,Karen E. Strunk,Douglas K. Graham,H. Shelton Earp +11 more
TL;DR: It is demonstrated that MerTK signaling in tumor-associated CD11b+ leukocytes promotes tumor growth by dampening acute inflammatory cytokines while inducing wound healing cytokines, and inhibition of MerTTK in the tumor microenvironment may have clinical benefit, stimulating antitumor immune responses or enhancing immunotherapeutic strategies.
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m 6 A mRNA Methylation Regulates Human β-Cell Biology in Physiological States and in Type 2 Diabetes
Dario F. De Jesus,Zijie Zhang,Zijie Zhang,Sevim Kahraman,Natalie K. Brown,Mengjie Chen,Jiang Hu,Manoj K. Gupta,Chuan He,Chuan He,Rohit N. Kulkarni +10 more
TL;DR: In this article, the m6A landscape segregates human type 2 diabetes (T2D) islets from controls significantly better than the transcriptome and that m6a is vital for β-cell biology.
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An antibody that locks HER3 in the inactive conformation inhibits tumor growth driven by HER2 or neuregulin.
Andrew Paul Garner,Carl Uli Bialucha,Elizabeth R. Sprague,Joan T. Garrett,Qing Sheng,Sharon Li,Olga Sineshchekova,Parmita Saxena,Cammie R. Sutton,Dongshu Chen,Yan Chen,Hui-Qin Wang,Jinsheng Liang,Rita Das,Rebecca Mosher,Jian Gu,Alan Huang,Nicole Haubst,Carolin Zehetmeier,Manuela Haberl,Winfried Elis,Christian Carsten Silvester Kunz,Analeah Heidt,Kara Herlihy,Joshua Murtie,Alwin Schuller,Carlos L. Arteaga,William R. Sellers,Seth Ettenberg +28 more
TL;DR: A novel HER3 monoclonal antibody that can neutralize multiple modes of HER3 activation is described, making it a superior candidate for clinical translation as a therapeutic candidate and establishing that LJM716 possesses a novel mechanism of action that, in combination with HER2- or EGFR-targeted agents, may leverage their clinical efficacy in ErbB-driven cancers.
Journal ArticleDOI
HER3 Is Required for HER2-Induced Preneoplastic Changes to the Breast Epithelium and Tumor Formation
David B. Vaught,Jamie C. Stanford,Christian D. Young,Donna J. Hicks,Frank Wheeler,Cammie Rinehart,Violeta Sanchez,John G. Koland,William J. Muller,Carlos L. Arteaga,Rebecca S. Cook +10 more
TL;DR: This work shows that mouse mammary specific models of Cre-mediated ErbB3 ablation prevent the progressive transformation of HER2-overexpressing mammary epithelium, and suggests that ErBB3 promotes Her2-induced changes in the breast epithelia before, during, and after tumor formation.
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MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling
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