Antitumor effects of the investigational selective MEK inhibitor TAK733 against cutaneous and uveal melanoma cell lines

Molecular Cancer

Research

Narsis Attar¹  Sybil Zachariah¹  Bartosz Chmielowski¹  Erika von Euw¹  Deborah JL Wong¹  Mohammad Atefi¹  Charles Ng¹  Stephen Mok¹  Connie Chu¹  Antoni Ribas²  Barry L Burgess³  Tara A McCannel⁴  Richard C Koya⁵  David I Lichter⁶  Elena Izmailova⁶ 

[1] Department of Medicine, Division of Hematology/Oncology, University of California Los Angeles (UCLA), Los Angeles, CA, USA;Department of Medicine, Division of Hematology/Oncology, University of California Los Angeles (UCLA), Los Angeles, CA, USA;Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, CA, USA;Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, CA, USA;Division of Hematology-Oncology, 11–934 Factor Building, UCLA Medical Center, 10833 Le Conte Avenue, 90095-1782, Los Angeles, CA, USA;Department of Ophthalmology, The Jules Stein Eye Institute, UCLA, Los Angeles, CA, USA;Department of Ophthalmology, The Jules Stein Eye Institute, UCLA, Los Angeles, CA, USA;Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, CA, USA;Jonsson Comprehensive Cancer Center at UCLA, Los Angeles, CA, USA;Millennium Pharmaceuticals, Inc., Cambridge, MA, USA;

关键词: Melanoma;    MEK inhibitor;    BRAF mutation;    Oncogenes;    MAPK signaling;   

DOI  :  10.1186/1476-4598-11-22

 received in 2011-08-21, accepted in 2012-04-19,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundTAK733 is a novel allosteric, non-ATP-binding, inhibitor of the BRAF substrates MEK-1/2.MethodsThe growth inhibitory effects of TAK733 were assessed in a panel of 27 cutaneous and five uveal melanoma cell lines genotyped for driver oncogenic mutations. Flow cytometry, Western blots and metabolic tracer uptake assays were used to characterize the changes induced by exposure to TAK733.ResultsFourteen cutaneous melanoma cell lines with different driver mutations were sensitive to the antiproliferative effects of TAK733, with a higher proportion of BRAFV600E mutant cell lines being highly sensitive with IC50s below 1 nM. The five uveal melanoma cell lines had GNAQ or GNA11 mutations and were either moderately or highly sensitive to TAK733. The tested cell lines wild type for NRAS, BRAF, GNAQ and GNA11 driver mutations were moderately to highly resistant to TAK733. TAK733 led to a decrease in pERK and G1 arrest in most of these melanoma cell lines regardless of their origin, driver oncogenic mutations and in vitro sensitivity to TAK733. MEK inhibition resulted in increase in pMEK more prominently in NRASQ61L mutant and GNAQ mutant cell lines than in BRAFV600E mutant cell lines. Uptake of the metabolic tracers FDG and FLT was inhibited by TAK733 in a manner that closely paralleled the in vitro sensitivity assays.ConclusionsThe MEK inhibitor TAK733 has antitumor properties in melanoma cell lines with different oncogenic mutations and these effects could be detectable by differential metabolic tracer uptake.

【 授权许可】

Unknown   
© von Euw et al.; licensee BioMed Central Ltd. 2012. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.