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Impact of receptor tyrosine kinase (RTK) ligands on sensitivity of human tumor-derived cell lines to kinase inhibitors

Analysis of the impact of RTK ligands on sensitivity of human tumor-derived cell lines to kinase inhibitors could guide combination therapy to prevent drug resistance. In about half of BRAF mutant melanoma cell lines, the RTK ligand hepatocyte growth factor/scatter factor (HGF/SF) induced c-Met proto-oncogene (MET; HGFR) expression and resistance to the BRAF inhibitor Zelboraf vemurafenib. In these cell lines, co-treatment with the MET kinase inhibitorXalkori crizotinib prevented resistance to Zelboraf. In patients with BRAF mutant melanoma, increased plasma HGF/SF levels correlated with poorer survival outcomes than normal HGF/SF levels. Next steps include analyzing the effects of RTK ligands on larger numbers of kinase-activated, human tumor-derived cell lines.
Zelboraf, from Daiichi Sankyo Co. Ltd., Chugai Pharmaceutical Co. Ltd. and Roche, is marketed to treat melanoma, in Phase I testing for colorectal cancer and in Phase II testing for thyroid cancer.

Xalkori from Pfizer Inc., which also inhibits anaplastic lymphoma kinase (ALK), is marketed to treat non-small cell lung cancer (NSCLC) and is in Phase I testing to treat solid tumors.

SciBX 5(31); doi:10.1038/scibx.2012.825
Published online Aug. 9, 2012

Patent and licensing status undisclosed

Wilson, T.R. et al. Nature; published online July 4, 2012;
Contact: Jeffrey Settleman, Genentech Inc., South San Francisco, Calif.