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1.
J Endocrinol Invest ; 41(5): 549-556, 2018 May.
Article in English | MEDLINE | ID: mdl-29043574

ABSTRACT

PURPOSE: Autoimmune diseases are typically associated with immune checkpoints blockade. This study aims at assessing, in real-life clinical practice, the prevalence and impact of thyroid disorders induced by immune checkpoint inhibitors. METHODS: 52 patients (30 F; age 61 ± 13 years) with advanced melanoma treated with ipilimumab (3 mg/kg i.v./3 weeks; 4 doses) were included. For disease progression, 29 (16 F) of them received nivolumab (3 mg/kg i.v./2 weeks) or pembrolizumab (2 mg/kg i.v./3 weeks). Thyroid function and autoimmunity were assessed before, after 6 weeks, at the end of ipilimumab, as well as before and every 3 months during nivolumab/pembrolizumab treatment. RESULTS: During ipilimumab, 7 (4 F) patients developed thyroid dysfunction (4 thyroiditis, 1 associated with hypothyroidism; 2 thyrotoxicosis in a previously euthyroid multinodular goiter; 1 hypothyroidism worsened). During PD1 inhibitors, 7 patients (3 F) developed hypothyroidism with severe manifestations in 6 of them; 3 patients suffered from euthyroid autoimmune thyroiditis from baseline, one after ipilimumab; 2 patients developed after transient thyrotoxicosis. Mean follow-up after anti-CTLA4 inhibitors treatment was 36 ± 28 months. Thyroid disorders occurred 45.1 ± 20.8 and 151 ± 67 days after the initiation of CTLA4 and PD1 inhibitors, respectively. Autoimmune disorders and BRAF mutation were associated with a better clinical response to CTLA4 followed by PD1 treatment. CONCLUSIONS: Immune checkpoint blockade is burdened by a high incidence of autoimmune thyroid dysfunction, which is often severe. Therefore, early and careful monitoring and, eventually, treatment are crucial to prevent the negative impact of thyroid dysfunction on the clinical outcome.


Subject(s)
Antibodies, Monoclonal, Humanized/adverse effects , Antibodies, Monoclonal/adverse effects , Antineoplastic Agents/adverse effects , CTLA-4 Antigen/antagonists & inhibitors , Melanoma/drug therapy , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Thyroid Diseases/chemically induced , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , Humans , Male , Middle Aged , Nivolumab , Prognosis , Prospective Studies , Referral and Consultation , Thyroid Diseases/pathology
2.
Oncogene ; 34(13): 1729-35, 2015 Mar 26.
Article in English | MEDLINE | ID: mdl-24837366

ABSTRACT

The ShcA adaptor protein is engaged by numerous receptor tyrosine kinases (RTKs) in breast cancer cells. Once activated, RTKs phosphorylate three key tyrosine phosphorylation sites (Y239, Y240 and Y317) within ShcA that creates a docking site for Grb2/SOS and Grb2/Gab-containing complexes to activate the MAPK and AKT signaling pathways, respectively. We previously demonstrated that a tyrosine to phenylalanine substitution of the ShcA tyrosine phosphorylation sites (Shc3F-Y239/240/313F) significantly impairs breast tumor growth and angiogenesis in transgenic mouse models, in part, through the regulation of vascular endothelial growth factor (VEGF) production. Despite this fact, the underlying molecular mechanisms by which ShcA transduces pro-tumorigenic signals in breast cancer cells remain poorly defined. In this study, we demonstrate that ShcA-dependent activation of AKT, but not the RAS/MAPK pathway, induces VEGF production by bolstering VEGF mRNA translation. Accordingly, ShcA drives breast tumor growth and angiogenesis in vivo in a 4E-BP-dependent manner. These findings establish ShcA as a biological bridge that links AKT activation downstream of RTKs to cap-dependent VEGF mRNA translation in order to promote mammary tumorigenesis.


Subject(s)
Adaptor Proteins, Signal Transducing/physiology , Breast Neoplasms/blood supply , Neovascularization, Pathologic/etiology , Phosphoproteins/physiology , Protein Biosynthesis , Proto-Oncogene Proteins c-akt/physiology , Shc Signaling Adaptor Proteins/physiology , Signal Transduction/physiology , Vascular Endothelial Growth Factor A/genetics , Animals , Cell Cycle Proteins , Female , Humans , Mice , Phosphatidylinositol 3-Kinases/physiology , RNA, Messenger/genetics , Src Homology 2 Domain-Containing, Transforming Protein 1 , Src Homology 2 Domain-Containing, Transforming Protein 3 , Vascular Endothelial Growth Factor A/biosynthesis
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