KPT-330 has antitumour activity against non-small cell lung cancer.

Abstract

BACKGROUND:

We investigated the biologic and pharmacologic activities of a chromosome region maintenance 1 (CRM1) inhibitor against human non-small cell lung cancer (NSCLC) cells both in vitro and in vivo.

METHODS:

The in vitro and in vivo effects of a novel CRM1 inhibitor (KPT-330) for a large number of anticancer parameters were evaluated using a large panel of 11 NSCLC cell lines containing different key driver mutations. Mice bearing human NSCLC xenografts were treated with KPT-330, and tumour growth was assessed.

RESULTS:

KPT-330 inhibited proliferation and induced cell cycle arrest and apoptosis-related proteins in 11 NSCLC cells lines. Moreover, the combination of KPT-330 with cisplatin synergistically enhanced the cell kill of the NSCLC cells in vitro. Human NSCLC tumours growing in immunodeficient mice were markedly inhibited by KPT-330. Also, KPT-330 was effective even against NSCLC cells with a transforming mutation of either exon 20 of EGFR, TP53, phosphatase and tensin homologue, RAS or PIK3CA, suggesting the drug might be effective against a variety of lung cancers irrespective of their driver mutation.

CONCLUSIONS:

Our results support clinical testing of KPT-330 as a novel therapeutic strategy for NSCLC.

• Authors: H Sun, N Hattori, W Chien, Q Sun, M Sudo, G L E-Ling, L Ding, S L Lim, S Shacham, M Kauffman, T Nakamaki, H P Koeffler
• Journal: British journal of cancer (Br J Cancer) Vol. 111 Issue 2 Pg. 281-91 (Jul 15 2014) ISSN: 1532-1827 [Electronic] England
• PMID: 24946002 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Hydrazines
• Karyopherins
• Receptors, Cytoplasmic and Nuclear
• Triazoles
• exportin 1 protein
• selinexor
• Cisplatin

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Antineoplastic Combined Chemotherapy Protocols (pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, pathology)
• Cell Growth Processes (drug effects)
• Cell Line, Tumor
• Cisplatin (pharmacology)
• G1 Phase (drug effects)
• Genes, p53
• Humans
• Hydrazines (pharmacology)
• Karyopherins (antagonists & inhibitors)
• Lung Neoplasms (drug therapy, genetics, pathology)
• Male
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Mutation
• Receptors, Cytoplasmic and Nuclear (antagonists & inhibitors)
• Triazoles (pharmacology)
• Xenograft Model Antitumor Assays