Nappi, Lucia (2016) Inhibition of Heat Shock Protein 27 (Hsp27) sensitizes Non-Small Cell Lung Cancer Cells to Epidermal Growth Factor Receptor (EGFR) inhibitors. [Tesi di dottorato]

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Tipologia del documento: Tesi di dottorato
Lingua: English
Titolo: Inhibition of Heat Shock Protein 27 (Hsp27) sensitizes Non-Small Cell Lung Cancer Cells to Epidermal Growth Factor Receptor (EGFR) inhibitors
Autori:
AutoreEmail
Nappi, Lucialucia.nappi@unina.it
Data: 31 Marzo 2016
Numero di pagine: 42
Istituzione: Università degli Studi di Napoli Federico II
Dipartimento: Medicina Clinica e Chirurgia
Scuola di dottorato: Medicina molecolare
Dottorato: Oncologia ed endocrinologia molecolare
Ciclo di dottorato: 28
Coordinatore del Corso di dottorato:
nomeemail
Santoro, Massimomasantor@unina.it
Tutor:
nomeemail
De Placido, Sabino[non definito]
Bianco, Roberto[non definito]
Data: 31 Marzo 2016
Numero di pagine: 42
Parole chiave: Hsp27, NSCLC, EGFR, targeted therapy, adaptive mechanisms of resistance, EGFR-inhibitors
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/06 - Oncologia medica
Depositato il: 11 Apr 2016 13:00
Ultima modifica: 17 Nov 2016 10:43
URI: http://www.fedoa.unina.it/id/eprint/11072

Abstract

Non-small cell lung cancer (NSCLC) is the most frequent cause of death from cancer worldwide. Despite the availability of active chemotherapy regimens and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors, all advanced patients develop recurrent disease after first-line therapy. While heat shock protein 27 (Hsp27) is a stress-induced chaperone that promotes acquired resistance in several cancers, its relationship to treatment resistance in NSCLC has not been defined. Understanding adaptive responses of acquired resistance will help guide new strategies to control NSCLC. Hsp27 levels were evaluated in an HCC827 erlotinib-resistant derived cell line (HCC-827Resistant), and sensitivity to erlotinib was examined in Hsp27 over-expressing A549 cells. The role of Hsp27 in both erlotinib and cytotoxic treatment resistance was evaluated in HCC827 and A549 NSCLC cells using the Hsp27 antisense drug OGX-427 and VPC-27, a new functional small molecule inhibitor of Hsp27. The effect of Hsp27 inhibitors in combination with erlotinib was also assessed in mice bearing A549 or HCC827 xenografts. Hsp27 is induced by erlotinib and protects NSCLC cells from treatment-induced apoptosis, while Hsp27 inhibition sensitizes NSCLC cells to erlotinib. Interestingly, increased resistance to erlotinib was observed when Hsp27 was increased either in HCC827 ER or over-expressing A549 cells. Combining OGX-427 or VPC-27 with erlotinib significantly enhanced antitumor effects in vitro and delayed NSCLC cells growth in vivo. These data indicate that treatment-induced Hsp27 (by inhibition of EGFR) contributes to the development of resistance, and provides pre-clinical proof-of-principle that inhibition of stress adaptive pathways mediated by Hsp27 enhances the activity of erlotinib in NSCLC.

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