ly3009120 has been researched along with Colorectal-Neoplasms* in 2 studies
2 other study(ies) available for ly3009120 and Colorectal-Neoplasms
| Article | Year |
|---|---|
Mouse PDX Trial Suggests Synergy of Concurrent Inhibition of RAF and EGFR in Colorectal Cancer with
Topics: Animals; Antineoplastic Agents; Biomarkers, Tumor; Cell Line, Tumor; Cetuximab; Colorectal Neoplasms; Disease Models, Animal; Drug Therapy, Combination; ErbB Receptors; Humans; Ligands; Mice; Mutation; Phenylurea Compounds; Polymorphism, Single Nucleotide; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Pyrimidines; Survival Rate; Treatment Outcome; Xenograft Model Antitumor Assays | 2017 |
LY3009120, a panRAF inhibitor, has significant anti-tumor activity in BRAF and KRAS mutant preclinical models of colorectal cancer.
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. Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Proliferation; Colorectal Neoplasms; Dose-Response Relationship, Drug; Extracellular Signal-Regulated MAP Kinases; Female; G1 Phase Cell Cycle Checkpoints; Genetic Predisposition to Disease; HCT116 Cells; HT29 Cells; Humans; Mutation; Phenotype; Phenylurea Compounds; Protein Kinase Inhibitors; Proto-Oncogene Proteins A-raf; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-raf; Proto-Oncogene Proteins p21(ras); Pyrimidines; Rats, Nude; RNA Interference; Time Factors; Transfection; Tumor Burden | 2017 |