Rosa, Roberta (2008) Analysis of the mechanisms of resistance to Epidermal growth factor receptor inhibitors and development of multiple targeted strategies. [Tesi di dottorato] (Unpublished)

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Item Type: Tesi di dottorato
Language: English
Title: Analysis of the mechanisms of resistance to Epidermal growth factor receptor inhibitors and development of multiple targeted strategies
Creators:
CreatorsEmail
Rosa, Robertarobertarosa2004@libero.it
Date: 29 November 2008
Number of Pages: 65
Institution: Università degli Studi di Napoli Federico II
Department: Endocrinologia ed oncologia molecolare e clinica
Doctoral School: Medicina molecolare
PHD name: Oncologia ed endocrinologia molecolare
PHD cycle: 21
PHD Coordinator:
nameemail
Vecchio, Giancarlovecchio@unina.it
Tutor:
nameemail
Tortora, Giampaologtortora@unina.it
Date: 29 November 2008
Number of Pages: 65
Uncontrolled Keywords: Drug Resistance, EGFR, Targeted Therapy
MIUR S.S.D.: Area 06 - Scienze mediche > MED/06 - Oncologia medica
Date Deposited: 09 Nov 2009 10:01
Last Modified: 30 Apr 2014 19:35
URI: http://www.fedoa.unina.it/id/eprint/3127

Abstract

Background. Primary and acquired resistance to selective Epidermal growth factor receptor (EGFR) inhibitors remains the most significant obstacle to the success of these targeted agents in cancer therapy. The mechanisms of resistance involve the activation of alternative signaling pathways able to bypass EGFR blockade, and Akt activation and VEGF induction have been described in EGFR inhibitor-resistant tumors. Combined inhibition of EGFR and other signaling proteins has become an effective approach to efficiently inhibit compensatory escape pathways, stimulating the search for further determinants of resistance as basis for novel therapeutic strategies. Aim of the study. The purpose of this study is to examine the signaling mechanisms operating in human cancers with intrinsic or acquired resistance to EGFR-targeted therapies and responsible for the lack of response to EGFR inhibitors. To this aim, we established human cancer cell lines with various degrees of EGFR expression and sensitivity to EGFR inhibitors and analyzed signal transducers under the control of EGFR-dependent and –independent pathways. Results. Multitargeted inhibitor vandetanib (ZD6474) inhibited human endothelial cells survival thanks to inhibition of both VEGFRs and EGFR signaling pathways. Vandetanib also inhibited the growth and the phosphorylation of Akt and its effector p70S6 kinase in both, wild-type and EGFR inhibitor-resistant human colon, prostate and breast cancer cells. We found that the resistant cell lines exhibit, as common features, VEGFR-1/Flt-1 overexpression, increased secretion of VEGF and placental growth factor (PlGF), and augmented migration capabilities, and that vandetanib is able to antagonize them. Accordingly, a new kinase assay revealed that in addition to VEGFR-2, RET and EGFR, vandetanib efficiently inhibits also VEGFR-1; this capability plays a key role in determining its activity on EGFR drugs-resistant tumors. The contribution of VEGFR-1 to the resistant phenotype was further supported by the demonstration that VEGFR-1 silencing in resistant cells restored sensitivity to anti-EGFR drugs and impaired migration capabilities, while exogenous VEGFR-1 overexpression in wild-type cells conferred resistance to these agents. Conclusions. This study demonstrates that VEGFR-1 contributes to anti-EGFR drugs resistance in different human cancer models. Moreover, vandetanib inhibits VEGFR-1 activation, cell proliferation and migration, suggesting its potential utility in patients resistant to EGFR inhibitors. Since vandetanib is successfully under investigation in several clinical studies, these data may be important for its clinical development.

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