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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2014

Open Access 01-12-2014 | Research

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

Authors: Amanda F Baker, Neale T Hanke, Barbara J Sands, Liliana Carbajal, Janet L Anderl, Linda L Garland

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2014

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Abstract

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 IC50 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 IC50 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.
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Metadata
Title
Carfilzomib demonstrates broad anti-tumor activity in pre-clinical non-small cell and small cell lung cancer models
Authors
Amanda F Baker
Neale T Hanke
Barbara J Sands
Liliana Carbajal
Janet L Anderl
Linda L Garland
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2014
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-014-0111-8

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