Document Detail


Truncated RAF kinases drive resistance to MET inhibition in MET-addicted cancer cells.
MedLine Citation:
PMID:  25473895     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
Constitutively active receptor tyrosine kinases (RTKs) are known oncogenic drivers and provide valuable therapeutic targets in many cancer types. However, clinical efficacy of RTK inhibitors is limited by intrinsic and acquired resistance. To identify genes conferring resistance to inhibition of the MET RTK, we conducted a forward genetics screen in the GTL-16 gastric cancer cell line, carrying MET amplification and exquisitely sensitive to MET inhibition. Cells were transduced with three different retroviral cDNA expression libraries and selected for growth in the presence of the MET inhibitor PHA-665752. Selected cells displayed robust and reproducible enrichment of library-derived cDNAs encoding truncated forms of RAF1 and BRAF proteins, whose silencing reversed the resistant phenotype. Transduction of naïve GTL-16 cells with truncated, but not full length, RAF1 and BRAF conferred in vitro and in vivo resistance to MET inhibitors, which could be reversed by MEK inhibition. Induction of resistance by truncated RAFs was confirmed in other MET-addicted cell lines, and further extended to EGFR-addicted cells. These data show that truncated RAF1 and BRAF proteins, recently described as products of genomic rearrangements in gastric cancer and other malignancies, have the ability to render neoplastic cells resistant to RTK-targeted therapy.
Authors:
Consalvo Petti; Gabriele Picco; Maria Luisa Martelli; Elena Trisolini; Enrico Bucci; Timothy Perera; Claudio Isella; Enzo Medico
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2014-11-15
Journal Detail:
Title:  Oncotarget     Volume:  -     ISSN:  1949-2553     ISO Abbreviation:  Oncotarget     Publication Date:  2014 Nov 
Date Detail:
Created Date:  2014-12-4     Completed Date:  -     Revised Date:  2014-12-5    
Medline Journal Info:
Nlm Unique ID:  101532965     Medline TA:  Oncotarget     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
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