title: Inhibition of melanoma development in the Nras((Q61K)) ::Ink4a(-/-)  mouse model by the small molecule BI-69A11.
abstract: 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.affiliation: Signal Transduction Program, Cancer Center, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Feng
authors.forename: Eric
authors.initials: E
authors.lastname: Lau
authors.forename: Marzia
authors.initials: M
authors.lastname: Scortegagna
authors.forename: Chelsea
authors.initials: C
authors.lastname: Ruller
authors.forename: Surya K
authors.initials: SK
authors.lastname: De
authors.forename: Elisa
authors.initials: E
authors.lastname: Barile
authors.forename: Stan
authors.initials: S
authors.lastname: Krajewski
authors.forename: Pedro
authors.initials: P
authors.lastname: Aza-Blanc
authors.forename: Roy
authors.initials: R
authors.lastname: Williams
authors.forename: Anthony B
authors.initials: AB
authors.lastname: Pinkerton
authors.forename: Michael
authors.initials: M
authors.lastname: Jackson
authors.forename: Lynda
authors.initials: L
authors.lastname: Chin
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pellecchia
authors.forename: Marcus
authors.initials: M
authors.lastname: Bosenberg
authors.forename: Ze'ev A
authors.initials: ZA
authors.lastname: Ronai
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics*; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency* / Q000378:metabolism; D004195:Disease Models, Animal; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007274:Injections, Intraperitoneal; D019394:Ki-67 Antigen / Q000378:metabolism; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D051379:Mice; D011230:Precancerous Conditions / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D015363:Quinolones / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D054852:Small Molecule Libraries / Q000494:pharmacology / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics*
chemical_list: C540767:3-(3-(1H-benzo(d)imidazol-2-yl)acryloyl)-6-chloro-4-phenylquinolin-2(1H)-one; D001562:Benzimidazoles; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019394:Ki-67 Antigen; D015363:Quinolones; D054852:Small Molecule Libraries; C482120:Braf protein, mouse; D048493:Proto-Oncogene Proteins B-raf; D017493:Leukocyte Common Antigens; D018631:ras Proteins