6 results on '"Castanaro, C"'
Search Results
2. FGFR3-TACC3 fusion proteins act as naturally occurring drivers of tumor resistance by functionally substituting for EGFR/ERK signaling
- Author
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Daly, C, Castanaro, C, Zhang, W, Zhang, Q, Wei, Y, Ni, M, Young, T M, Zhang, L, Burova, E, and Thurston, G
- Abstract
The epidermal growth factor receptor (EGFR) is a clinically validated target in head and neck squamous cell carcinoma (HNSCC), where EGFR-blocking antibodies are approved for first-line treatment. However, as with other targeted therapies, intrinsic/acquired resistance mechanisms limit efficacy. In the FaDu HNSCC xenograft model, we show that combined blockade of EGFR and ERBB3 promotes rapid tumor regression, followed by the eventual outgrowth of resistant cells. RNA sequencing revealed that resistant cells express FGFR3-TACC3 fusion proteins, which were validated as drivers of the resistant phenotype by several approaches, including CRISPR-mediated inactivation of FGFR3-TACC3 fusion genes. Interestingly, analysis of signaling in resistant cell lines demonstrated that FGFR3-TACC3 fusion proteins promote resistance by preferentially substituting for EGFR/RAS/ERK signaling rather than ERBB3/PI3K/AKT signaling. Furthermore, although FGFR3-TACC3 fusion proteins promote resistance of additional EGFR-dependent HNSCC and lung cancer cell lines to EGFR blockade, they are unable to compensate for inhibition of PI3K signaling in PIK3CA-mutant HNSCC cell lines. Validation of FGFR3-TACC3 fusion proteins as endogenous drivers of resistance in our screen provides strong evidence that these fusions are capable of substituting for EGFR signaling. Thus, FGFR3-TACC3 fusion proteins may represent a novel mechanism of acquired resistance in EGFR-dependent cancers of multiple cell lineages.
- Published
- 2017
- Full Text
- View/download PDF
3. Autophagy protects tumors from T cell-mediated cytotoxicity via inhibition of TNFα-induced apoptosis.
- Author
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Young TM, Reyes C, Pasnikowski E, Castanaro C, Wong C, Decker CE, Chiu J, Song H, Wei Y, Bai Y, Zambrowicz B, Thurston G, and Daly C
- Subjects
- Animals, Caspase 8 metabolism, Cell Line, Tumor, Fas-Associated Death Domain Protein genetics, Fas-Associated Death Domain Protein metabolism, Gene Editing, Gene Knockdown Techniques, Mice, Signal Transduction, Tumor Necrosis Factor-alpha pharmacology, Apoptosis drug effects, Apoptosis immunology, Autophagy, Cytotoxicity, Immunologic, T-Lymphocytes immunology, T-Lymphocytes metabolism, Tumor Necrosis Factor-alpha metabolism
- Abstract
Although T cell checkpoint inhibitors have transformed the treatment of cancer, the molecular determinants of tumor cell sensitivity to T cell-mediated killing need further elucidation. Here, we describe a mouse genome-scale CRISPR knockout screen that identifies tumor cell TNFα signaling as an important component of T cell-induced apoptosis, with NF-κB signaling and autophagy as major protective mechanisms. Knockout of individual autophagy genes sensitized tumor cells to killing by T cells that were activated via specific TCR or by a CD3 bispecific antibody. Conversely, inhibition of mTOR signaling, which results in increased autophagic activity, protected tumor cells from T cell killing. Autophagy functions at a relatively early step in the TNFα signaling pathway, limiting FADD-dependent caspase-8 activation. Genetic inactivation of tumor cell autophagy enhanced the efficacy of immune checkpoint blockade in mouse tumor models. Thus, targeting the protective autophagy pathway might sensitize tumors to T cell-engaging immunotherapies in the clinic., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2020
- Full Text
- View/download PDF
4. Angiopoietins bind thrombomodulin and inhibit its function as a thrombin cofactor.
- Author
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Daly C, Qian X, Castanaro C, Pasnikowski E, Jiang X, Thomson BR, Quaggin SE, Papadopoulos N, Wei Y, Rudge JS, Thurston G, Yancopoulos GD, and Davis S
- Subjects
- Angiopoietin-1 blood, Angiopoietin-1 genetics, Angiopoietin-2 genetics, Animals, Blood Platelets drug effects, Blood Platelets metabolism, COS Cells, Carboxypeptidase B2 metabolism, Chlorocebus aethiops, Human Umbilical Vein Endothelial Cells, Humans, Mice, Mice, Inbred C57BL, Platelet Factor 4 metabolism, Protein Binding, Protein C metabolism, RNA Interference, RNA, Small Interfering metabolism, Receptor, TIE-2 antagonists & inhibitors, Receptor, TIE-2 genetics, Receptor, TIE-2 metabolism, Recombinant Proteins biosynthesis, Recombinant Proteins genetics, Thrombin chemistry, Thrombin pharmacology, Thrombomodulin genetics, Angiopoietin-1 metabolism, Angiopoietin-2 metabolism, Thrombin metabolism, Thrombomodulin metabolism
- Abstract
Angiopoietin-1 (Ang1) and Angiopoietin-2 (Ang2) are ligands for Tie2, an endothelial-specific receptor tyrosine kinase that is an essential regulator of angiogenesis. Here we report the identification, via expression cloning, of thrombomodulin (TM) as another receptor for Ang1 and Ang2. Thrombomodulin is an endothelial cell surface molecule that plays an essential role as a coagulation inhibitor via its function as a cofactor in the thrombin-mediated activation of protein C, an anticoagulant protein, as well as thrombin-activatable fibrinolysis inhibitor (TAFI). Ang1 and Ang2 inhibited the thrombin/TM-mediated generation of activated protein C and TAFI in cultured endothelial cells, and inhibited the binding of thrombin to TM in vitro. Ang2 appears to bind TM with higher affinity than Ang1 and is a more potent inhibitor of TM function. Consistent with a potential role for angiopoietins in coagulation, administration of thrombin to mice rapidly increased plasma Ang1 levels, presumably reflecting release from activated platelets (previously shown to contain high levels of Ang1). In addition, Ang1 levels were significantly elevated in plasma prepared from wound blood, suggesting that Ang1 is released from activated platelets at sites of vessel injury. Our results imply a previously undescribed role for angiopoietins in the regulation of hemostasis.
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- 2018
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5. ERBB3/HER2 signaling promotes resistance to EGFR blockade in head and neck and colorectal cancer models.
- Author
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Zhang L, Castanaro C, Luan B, Yang K, Fan L, Fairhurst JL, Rafique A, Potocky TB, Shan J, Delfino FJ, Shi E, Huang T, Martin JH, Chen G, Macdonald D, Rudge JS, Thurston G, and Daly C
- Subjects
- Animals, Antibodies, Blocking pharmacology, Antibodies, Monoclonal pharmacology, Antibodies, Monoclonal, Humanized pharmacology, Cell Line, Tumor, Colorectal Neoplasms drug therapy, Colorectal Neoplasms pathology, Disease Models, Animal, Head and Neck Neoplasms drug therapy, Head and Neck Neoplasms pathology, Humans, Mice, Protein Binding, Proto-Oncogene Proteins c-akt metabolism, Receptor, ErbB-2 antagonists & inhibitors, Receptor, ErbB-3 antagonists & inhibitors, Tumor Burden drug effects, Xenograft Model Antitumor Assays, Colorectal Neoplasms metabolism, Drug Resistance, Neoplasm, ErbB Receptors antagonists & inhibitors, Head and Neck Neoplasms metabolism, Receptor, ErbB-2 metabolism, Receptor, ErbB-3 metabolism
- Abstract
EGFR blocking antibodies are approved for the treatment of colorectal cancer and head and neck squamous cell carcinoma (HNSCC). Although ERBB3 signaling has been proposed to limit the effectiveness of EGFR inhibitors, the underlying molecular mechanisms are not fully understood. To gain insight into these mechanisms, we generated potent blocking antibodies against ERBB3 (REGN1400) and EGFR (REGN955). We show that EGFR and ERBB3 are coactivated in multiple HNSCC cell lines and that combined blockade of EGFR and ERBB3 inhibits growth of these cell lines more effectively than blockade of either receptor alone. Blockade of EGFR with REGN955 strongly inhibited activation of ERK in HNSCC cell lines, whereas blockade of ERBB3 with REGN1400 strongly inhibited activation of Akt; only the combination of the 2 antibodies blocked both of these essential downstream pathways. We used a HER2 blocking antibody to show that ERBB3 phosphorylation in HNSCC and colorectal cancer cells is strictly dependent on association with HER2, but not EGFR, and that neuregulin 1 activates ERBB3/HER2 signaling to reverse the effect of EGFR blockade on colorectal cancer cell growth. Finally, although REGN1400 and REGN955 as single agents slowed the growth of HNSCC and colorectal cancer xenografts, the combination of REGN1400 plus REGN955 caused significant tumor regression. Our results indicate that activation of the Akt survival pathway by ERBB3/HER2 limits the effectiveness of EGFR inhibition, suggesting that REGN1400, which is currently in a phase I clinical trial, could provide benefit when combined with EGFR blocking antibodies.
- Published
- 2014
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6. Angiopoietin-2 functions as a Tie2 agonist in tumor models, where it limits the effects of VEGF inhibition.
- Author
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Daly C, Eichten A, Castanaro C, Pasnikowski E, Adler A, Lalani AS, Papadopoulos N, Kyle AH, Minchinton AI, Yancopoulos GD, and Thurston G
- Subjects
- Animals, Disease Models, Animal, Humans, Mice, Neoplasms, Experimental blood supply, Neovascularization, Pathologic metabolism, Signal Transduction physiology, Transplantation, Heterologous, Vascular Endothelial Growth Factor A metabolism, Angiopoietin-2 metabolism, Gene Expression Regulation, Neoplastic physiology, Neoplasms, Experimental metabolism, Receptor, TIE-2 agonists, Receptor, TIE-2 metabolism, Vascular Endothelial Growth Factor A antagonists & inhibitors
- Abstract
The angiopoietins Ang1 (ANGPT1) and Ang2 (ANGPT2) are secreted factors that bind to the endothelial cell-specific receptor tyrosine kinase Tie2 (TEK) and regulate angiogenesis. Ang1 activates Tie2 to promote blood vessel maturation and stabilization. In contrast, Ang2, which is highly expressed by tumor endothelial cells, is thought to inhibit Tie2 activity and destabilize blood vessels, thereby facilitating VEGF-dependent vessel growth. Here, we show that the inhibition of tumor xenograft growth caused by an Ang2-specific antibody (REGN910) is reversed by systemic administration of the Tie2 agonist Ang1. These results indicate that Ang2 blockade inhibits tumor growth by decreasing Tie2 activity, showing that Ang2 is a Tie2 activator. REGN910 treatment of tumors resulted in increased expression of genes that are repressed by Tie2 activation, providing further evidence that REGN910 inhibits Tie2 signaling. Combination treatment with REGN910 plus the VEGF blocker aflibercept reduced tumor vascularity and tumor perfusion more dramatically than either single agent, resulting in more extensive tumor cell death and more potent inhibition of tumor growth. Challenging the prevailing model of Ang2 as a destabilizing factor, our findings indicate that Ang2 plays a protective role in tumor endothelial cells by activating Tie2, thereby limiting the antivascular effects of VEGF inhibition. Thus, blockade of Ang2 might enhance the clinical benefits currently provided by anti-VEGF agents. .
- Published
- 2013
- Full Text
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