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: Eliza Vakana, Susan Pratt, Wayne Blosser, Michele Dowless, Nicholas Simpson, Xiu-Juan Yuan, Susan Jaken, Jason Manro, Jennifer Stephens, Youyan Zhang, Lysiane Huber, Sheng-Bin Peng, Louis F Stancato
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 6 Pg. 9251-9266 (Feb 07 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 27999210 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• KRAS protein, human
• LY3009120
• Phenylurea Compounds
• Protein Kinase Inhibitors
• Pyrimidines
• BRAF protein, human
• Proto-Oncogene Proteins A-raf
• Proto-Oncogene Proteins B-raf
• Proto-Oncogene Proteins c-akt
• Proto-Oncogene Proteins c-raf
• Extracellular Signal-Regulated MAP Kinases
• Proto-Oncogene Proteins p21(ras)

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Proliferation (drug effects)
• Colorectal Neoplasms (drug therapy, enzymology, genetics, pathology)
• Dose-Response Relationship, Drug
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• G1 Phase Cell Cycle Checkpoints (drug effects)
• Genetic Predisposition to Disease
• HCT116 Cells
• HT29 Cells
• Humans
• Mutation
• Phenotype
• Phenylurea Compounds (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins A-raf (antagonists & inhibitors, genetics, metabolism)
• Proto-Oncogene Proteins B-raf (antagonists & inhibitors, genetics, metabolism)
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-raf (antagonists & inhibitors, genetics, metabolism)
• Proto-Oncogene Proteins p21(ras) (genetics)
• Pyrimidines (pharmacology)
• RNA Interference
• Rats, Nude
• Time Factors
• Transfection
• Tumor Burden (drug effects)