Abstract:
:One-third of all human cancers harbor somatic RAS mutations. This leads to aberrant activation of downstream signaling pathways involving the RAF kinases. Current ATP-competitive RAF inhibitors are active in cancers with somatic RAF mutations, such as BRAF(V600) mutant melanomas. However, they paradoxically promote the growth of RAS mutant tumors, partly due to the complex interplay between different homo- and heterodimers of A-RAF, B-RAF, and C-RAF. Based on pathway analysis and structure-guided compound identification, we describe the natural product cotylenin-A (CN-A) as stabilizer of the physical interaction of C-RAF with 14-3-3 proteins. CN-A binds to inhibitory 14-3-3 interaction sites of C-RAF, pSer233, and pSer259, but not to the activating interaction site, pSer621. While CN-A alone is inactive in RAS mutant cancer models, combined treatment with CN-A and an anti-EGFR antibody synergistically suppresses tumor growth in vitro and in vivo. This defines a novel pharmacologic strategy for treatment of RAS mutant cancers.
journal_name
ACS Chem Bioljournal_title
ACS chemical biologyauthors
Molzan M,Kasper S,Röglin L,Skwarczynska M,Sassa T,Inoue T,Breitenbuecher F,Ohkanda J,Kato N,Schuler M,Ottmann Cdoi
10.1021/cb4003464subject
Has Abstractpub_date
2013-09-20 00:00:00pages
1869-75issue
9eissn
1554-8929issn
1554-8937journal_volume
8pub_type
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