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Carfilzomib demonstrates broad anti-tumor activity in pre-clinical non-small cell and small cell lung cancer models

BACKGROUND: Carfilzomib (CFZ) is a proteasome inhibitor that selectively and irreversibly binds to its target and has been approved in the US for treatment of relapsed and refractory multiple myeloma. Phase 1B studies of CFZ reported signals of clinical activity in solid tumors, including small cell...

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Autores principales: Baker, Amanda F, Hanke, Neale T, Sands, Barbara J, Carbajal, Liliana, Anderl, Janet L, Garland, Linda L
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4304157/
https://www.ncbi.nlm.nih.gov/pubmed/25612802
http://dx.doi.org/10.1186/s13046-014-0111-8
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author Baker, Amanda F
Hanke, Neale T
Sands, Barbara J
Carbajal, Liliana
Anderl, Janet L
Garland, Linda L
author_facet Baker, Amanda F
Hanke, Neale T
Sands, Barbara J
Carbajal, Liliana
Anderl, Janet L
Garland, Linda L
author_sort Baker, Amanda F
collection PubMed
description BACKGROUND: Carfilzomib (CFZ) is a proteasome inhibitor that selectively and irreversibly binds to its target and has been approved in the US for treatment of relapsed and refractory multiple myeloma. Phase 1B studies of CFZ reported signals of clinical activity in solid tumors, including small cell lung cancer (SCLC). The aim of this study was to investigate the activity of CFZ in lung cancer models. METHODS: A diverse panel of human lung cancer cell lines and a SHP77 small cell lung cancer xenograft model were used to investigate the anti-tumor activity of CFZ. RESULTS: CFZ treatment inhibited both the constitutive proteasome and the immunoproteasome in lung cancer cell lines. CFZ had marked anti-proliferative activity in A549, H1993, H520, H460, and H1299 non-small cell lung cancer (NSCLC) cell lines, with IC(50) values after 96 hour exposure from <1.0 nM to 36 nM. CFZ had more variable effects in the SHP77 and DMS114 SCLC cell lines, with IC(50) values at 96 hours from <1 nM to 203 nM. Western blot analysis of CFZ-treated H1993 and SHP77 cells showed cleavage of poly ADP ribose polymerase (PARP) and caspase-3, indicative of apoptosis, and induction of microtubule-associated protein-1 light chain-3B (LC3B), indicative of autophagy. In SHP77 flank xenograft tumors, CFZ monotherapy inhibited tumor growth and prolonged survival, while no additive or synergistic anti-tumor efficacy was observed for CFZ + cisplatin (CDDP). CONCLUSIONS: CFZ demonstrated anti-proliferative activity in lung cancer cell lines in vitro and resulted in a significant survival advantage in mice with SHP77 SCLC xenografts, supporting further pre-clinical and clinical investigations of CFZ in NSCLC and SCLC. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13046-014-0111-8) contains supplementary material, which is available to authorized users.
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spelling pubmed-43041572015-01-24 Carfilzomib demonstrates broad anti-tumor activity in pre-clinical non-small cell and small cell lung cancer models Baker, Amanda F Hanke, Neale T Sands, Barbara J Carbajal, Liliana Anderl, Janet L Garland, Linda L J Exp Clin Cancer Res Research BACKGROUND: Carfilzomib (CFZ) is a proteasome inhibitor that selectively and irreversibly binds to its target and has been approved in the US for treatment of relapsed and refractory multiple myeloma. Phase 1B studies of CFZ reported signals of clinical activity in solid tumors, including small cell lung cancer (SCLC). The aim of this study was to investigate the activity of CFZ in lung cancer models. METHODS: A diverse panel of human lung cancer cell lines and a SHP77 small cell lung cancer xenograft model were used to investigate the anti-tumor activity of CFZ. RESULTS: CFZ treatment inhibited both the constitutive proteasome and the immunoproteasome in lung cancer cell lines. CFZ had marked anti-proliferative activity in A549, H1993, H520, H460, and H1299 non-small cell lung cancer (NSCLC) cell lines, with IC(50) values after 96 hour exposure from <1.0 nM to 36 nM. CFZ had more variable effects in the SHP77 and DMS114 SCLC cell lines, with IC(50) values at 96 hours from <1 nM to 203 nM. Western blot analysis of CFZ-treated H1993 and SHP77 cells showed cleavage of poly ADP ribose polymerase (PARP) and caspase-3, indicative of apoptosis, and induction of microtubule-associated protein-1 light chain-3B (LC3B), indicative of autophagy. In SHP77 flank xenograft tumors, CFZ monotherapy inhibited tumor growth and prolonged survival, while no additive or synergistic anti-tumor efficacy was observed for CFZ + cisplatin (CDDP). CONCLUSIONS: CFZ demonstrated anti-proliferative activity in lung cancer cell lines in vitro and resulted in a significant survival advantage in mice with SHP77 SCLC xenografts, supporting further pre-clinical and clinical investigations of CFZ in NSCLC and SCLC. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13046-014-0111-8) contains supplementary material, which is available to authorized users. BioMed Central 2014-12-31 /pmc/articles/PMC4304157/ /pubmed/25612802 http://dx.doi.org/10.1186/s13046-014-0111-8 Text en © Baker et al.; licensee BioMed Central. 2014 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Baker, Amanda F
Hanke, Neale T
Sands, Barbara J
Carbajal, Liliana
Anderl, Janet L
Garland, Linda L
Carfilzomib demonstrates broad anti-tumor activity in pre-clinical non-small cell and small cell lung cancer models
title Carfilzomib demonstrates broad anti-tumor activity in pre-clinical non-small cell and small cell lung cancer models
title_full Carfilzomib demonstrates broad anti-tumor activity in pre-clinical non-small cell and small cell lung cancer models
title_fullStr Carfilzomib demonstrates broad anti-tumor activity in pre-clinical non-small cell and small cell lung cancer models
title_full_unstemmed Carfilzomib demonstrates broad anti-tumor activity in pre-clinical non-small cell and small cell lung cancer models
title_short Carfilzomib demonstrates broad anti-tumor activity in pre-clinical non-small cell and small cell lung cancer models
title_sort carfilzomib demonstrates broad anti-tumor activity in pre-clinical non-small cell and small cell lung cancer models
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4304157/
https://www.ncbi.nlm.nih.gov/pubmed/25612802
http://dx.doi.org/10.1186/s13046-014-0111-8
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