title: LY3009120, a panRAF inhibitor, has significant anti-tumor activity in BRAF and KRAS mutant preclinical models of colorectal cancer.
abstract: Activating mutations in the KRAS and BRAF genes, leading to hyperactivation of the RAS/RAF/MAPK oncogenic signaling cascade, are common in patients with colorectal cancer (CRC). While selective BRAF inhibitors are efficacious in BRAFmut melanoma, they have limited efficacy in BRAFmut CRC patients. In a RASmut background, selective BRAF inhibitors are contraindicated due to paradoxical activation of the MAPK pathway through potentiation of CRAF kinase activity. A way to overcome such paradoxical activation is through concurrent inhibition of the kinase activity of both RAF isoforms. Here, we further examined the effects of LY3009120, a panRAF and RAF dimer inhibitor, in human models of CRC with various mutational backgrounds. We demonstrate that LY3009120 induced anti-proliferative effects in BRAFmut and KRASmut CRC cell lines through G1-cell cycle arrest. The anti-proliferative effects of LY3009120 in KRASmut CRC cell lines phenocopied molecular inhibition of RAF isoforms by simultaneous siRNA-mediated knockdown of ARAF, BRAF and CRAF. Additionally, LY3009120 displayed significant activity in in vivo BRAFmut and KRASmut CRC xenograft models. Examination of potential resistance to LY3009120 demonstrated RAF-independent ERK and AKT activation in the KRASmut CRC cell line HCT 116. These findings describe the preclinical activity of a panRAF inhibitor in a BRAFmut and KRASmut CRC setting.
authors.affiliation: Oncology Discovery Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Eliza
authors.initials: E
authors.lastname: Vakana
authors.affiliation: Oncology Discovery Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Pratt
authors.affiliation: Oncology Discovery Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Wayne
authors.initials: W
authors.lastname: Blosser
authors.affiliation: Oncology Discovery Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Michele
authors.initials: M
authors.lastname: Dowless
authors.affiliation: Discovery Research, Advanced Testing Laboratory, Cincinnati, OH 45242, USA.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Simpson
authors.affiliation: Cell Technologies, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Xiu-Juan
authors.initials: XJ
authors.lastname: Yuan
authors.affiliation: Cell Technologies, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Jaken
authors.affiliation: Discovery Statistics, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Manro
authors.affiliation: Oncology Discovery Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Stephens
authors.affiliation: Oncology Discovery Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Youyan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Oncology Discovery Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Lysiane
authors.initials: L
authors.lastname: Huber
authors.affiliation: Oncology Discovery Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Sheng-Bin
authors.initials: SB
authors.lastname: Peng
authors.affiliation: Oncology Discovery Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
authors.forename: Louis F
authors.initials: LF
authors.lastname: Stancato
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D045325:HCT116 Cells; D019073:HT29 Cells; D006801:Humans; D009154:Mutation; D010641:Phenotype; D010671:Phenylurea Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048491:Proto-Oncogene Proteins A-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D011743:Pyrimidines / Q000494:pharmacology*; D034622:RNA Interference; D011923:Rats, Nude; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; C117307:KRAS protein, human; C000600963:LY3009120; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; C482119:BRAF protein, human; D048491:Proto-Oncogene Proteins A-raf; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D019908:Proto-Oncogene Proteins c-raf; D048049:Extracellular Signal-Regulated MAP Kinases; D016283:Proto-Oncogene Proteins p21(ras)
keywords: RAF; RAS; colorectal cancer; signaling pathways; xenograft models