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

Journal of Experimental & Clinical Cancer Research

Linda L Garland¹  Janet L Anderl²  Liliana Carbajal¹  Barbara J Sands¹  Neale T Hanke¹  Amanda F Baker¹ 

[1] University of Arizona Cancer Center, College of Medicine, Section of Hematology/Oncology, 1515 N Campbell Ave, Tucson, AZ, USA;Onyx Pharmaceuticals, Inc., an Amgen subsidiary, South San Francisco, CA, USA

关键词: Cisplatin;    Lung cancer;    Proteasome inhibitor;    Carfilzomib;   

Others  :  1135988
DOI  :  10.1186/s13046-014-0111-8

 received in 2014-08-28, accepted in 2014-12-11,  发布年份 2014

【 摘 要 】

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.

【 授权许可】

   
2014 Baker et al.; licensee BioMed Central.

【 图 表 】

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