Document Detail

Foretinib is a potent inhibitor of oncogenic ROS1 fusion proteins.
MedLine Citation:
PMID:  24218589     Owner:  NLM     Status:  MEDLINE    
The rapidly growing recognition of the role of oncogenic ROS1 fusion proteins in the malignant transformation of multiple cancers, including lung adenocarcinoma, cholangiocarcinoma, and glioblastoma, is driving efforts to develop effective ROS1 inhibitors for use as molecularly targeted therapy. Using a multidisciplinary approach involving small molecule screening in combination with in vitro and in vivo tumor models, we show that foretinib (GSK1363089) is a more potent ROS1 inhibitor than crizotinib (PF-02341066), an ALK/ROS inhibitor currently in clinical evaluation for lung cancer patients harboring ROS1 rearrangements. Whereas crizotinib has demonstrated promising early results in patients with ROS1-rearranged non-small-cell lung carcinoma, recently emerging clinical evidence suggests that patients may develop crizotinib resistance due to acquired point mutations in the kinase domain of ROS1, thus necessitating identification of additional potent ROS1 inhibitors for therapeutic intervention. We confirm that the ROS1(G2032R) mutant, recently reported in clinical resistance to crizotinib, retains foretinib sensitivity at concentrations below safe, clinically achievable levels. Furthermore, we use an accelerated mutagenesis screen to preemptively identify mutations in the ROS1 kinase domain that confer resistance to crizotinib and demonstrate that these mutants also remain foretinib sensitive. Taken together, our data strongly suggest that foretinib is a highly effective ROS1 inhibitor, and further clinical investigation to evaluate its potential therapeutic benefit for patients with ROS1-driven malignancies is warranted.
Monika A Davare; Anna Saborowski; Christopher A Eide; Cristina Tognon; Rebecca L Smith; Johannes Elferich; Anupriya Agarwal; Jeffrey W Tyner; Ujwal P Shinde; Scott W Lowe; Brian J Druker
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2013-11-11
Journal Detail:
Title:  Proceedings of the National Academy of Sciences of the United States of America     Volume:  110     ISSN:  1091-6490     ISO Abbreviation:  Proc. Natl. Acad. Sci. U.S.A.     Publication Date:  2013 Nov 
Date Detail:
Created Date:  2013-11-27     Completed Date:  2014-01-27     Revised Date:  2014-06-26    
Medline Journal Info:
Nlm Unique ID:  7505876     Medline TA:  Proc Natl Acad Sci U S A     Country:  United States    
Other Details:
Languages:  eng     Pagination:  19519-24     Citation Subset:  IM    
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MeSH Terms
Anilides / pharmacology*
Base Sequence
Cell Line, Tumor
Cell Survival / drug effects
DNA Primers / genetics
Flow Cytometry
Molecular Sequence Data
Oncogenes / genetics*
Proto-Oncogene Proteins / antagonists & inhibitors*,  genetics
Quinolines / pharmacology*
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors*,  genetics
Sequence Analysis, DNA
Grant Support
P01 CA013106/CA/NCI NIH HHS; P30 CA008748/CA/NCI NIH HHS; //Howard Hughes Medical Institute
Reg. No./Substance:
0/Anilides; 0/DNA Primers; 0/GSK 1363089; 0/Proto-Oncogene Proteins; 0/Quinolines; EC Protein-Tyrosine Kinases; EC protein, mouse

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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