Document Detail


Inhibition of melanoma development in the Nras((Q61K)) ::Ink4a(-/-) mouse model by the small molecule BI-69A11.
MedLine Citation:
PMID:  23035722     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
To date, there are no effective therapies for tumors bearing NRAS mutations, which are present in 15-20% of human melanomas. Here we extend our earlier studies where we demonstrated that the small molecule BI-69A11 inhibits the growth of melanoma cell lines. Gene expression analysis revealed the induction of interferon- and cell death-related genes that were associated with responsiveness of melanoma cell lines to BI-69A11. Strikingly, the administration of BI-69A11 inhibited melanoma development in genetically modified mice bearing an inducible form of activated Nras and a deletion of the Ink4a gene (Nras((Q61K)) ::Ink4a(-/-) ). Biweekly administration of BI-69A11 starting at 10 weeks or as late as 24 weeks after the induction of mutant Nras expression inhibited melanoma development (100 and 36%, respectively). BI-69A11 treatment did not inhibit the development of histiocytic sarcomas, which constitute about 50% of the tumors in this model. BI-69A11-resistant Nras((Q61K)) ::Ink4a(-/-) tumors exhibited increased CD45 expression, reflective of immune cell infiltration and upregulation of gene networks associated with the cytoskeleton, DNA damage response, and small molecule transport. The ability to attenuate the development of NRAS mutant melanomas supports further development of BI-69A11 for clinical assessment.
Authors:
Yongmei Feng; Eric Lau; Marzia Scortegagna; Chelsea Ruller; Surya K De; Elisa Barile; Stan Krajewski; Pedro Aza-Blanc; Roy Williams; Anthony B Pinkerton; Michael Jackson; Lynda Chin; Maurizio Pellecchia; Marcus Bosenberg; Ze'ev A Ronai
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-11-02
Journal Detail:
Title:  Pigment cell & melanoma research     Volume:  26     ISSN:  1755-148X     ISO Abbreviation:  Pigment Cell Melanoma Res     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2012-12-20     Completed Date:  2013-06-13     Revised Date:  2014-04-16    
Medline Journal Info:
Nlm Unique ID:  101318927     Medline TA:  Pigment Cell Melanoma Res     Country:  England    
Other Details:
Languages:  eng     Pagination:  136-42     Citation Subset:  IM    
Copyright Information:
© 2012 John Wiley & Sons A/S.
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MeSH Terms
Descriptor/Qualifier:
Amino Acid Substitution / genetics*
Animals
Antigens, CD45 / metabolism
Benzimidazoles / administration & dosage,  pharmacology,  therapeutic use*
Cell Proliferation / drug effects
Cyclin-Dependent Kinase Inhibitor p16 / deficiency*,  metabolism
Disease Models, Animal
Gene Expression Regulation, Neoplastic / drug effects
Humans
Injections, Intraperitoneal
Ki-67 Antigen / metabolism
Melanoma / drug therapy*,  genetics,  pathology
Mice
Precancerous Conditions / drug therapy*,  genetics,  pathology
Proto-Oncogene Proteins B-raf / genetics
Quinolones / administration & dosage,  pharmacology,  therapeutic use*
Skin Neoplasms / drug therapy*,  genetics,  pathology
Small Molecule Libraries / pharmacology,  therapeutic use
Xenograft Model Antitumor Assays
ras Proteins / genetics*
Grant Support
ID/Acronym/Agency:
CA099961/CA/NCI NIH HHS; CA128814/CA/NCI NIH HHS; P01 CA128814/CA/NCI NIH HHS; P30 CA030199/CA/NCI NIH HHS; R01 CA051995/CA/NCI NIH HHS; R01 CA099961/CA/NCI NIH HHS; R01 CA117927/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/3-(3-(1H-benzo(d)imidazol-2-yl)acryloyl)-6-chloro-4-phenylquinolin-2(1H)-one; 0/Benzimidazoles; 0/Cyclin-Dependent Kinase Inhibitor p16; 0/Ki-67 Antigen; 0/Quinolones; 0/Small Molecule Libraries; EC 2.7.11.1/Braf protein, mouse; EC 2.7.11.1/Proto-Oncogene Proteins B-raf; EC 3.1.3.48/Antigens, CD45; EC 3.6.5.2/ras Proteins
Comments/Corrections

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