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LY3009120, a panRAF inhibitor, has significant anti-tumor activity in BRAF and KRAS mutant preclinical models of colorectal cancer
- Source :
- Oncotarget
- Publication Year :
- 2016
- Publisher :
- Impact Journals LLC, 2016.
-
Abstract
- // Eliza Vakana 1, * , Susan Pratt 1, * , Wayne Blosser 1 , Michele Dowless 1 , Nicholas Simpson 2 , Xiu-Juan Yuan 3 , Susan Jaken 3 , Jason Manro 4 , Jennifer Stephens 1 , Youyan Zhang 1 , Lysiane Huber 1 , Sheng-Bin Peng 1 , Louis F. Stancato 1 1 Oncology Discovery Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA 2 Discovery Research, Advanced Testing Laboratory, Cincinnati, OH 45242, USA 3 Cell Technologies, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA 4 Discovery Statistics, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA * These authors contributed equally to this work Correspondence to: Louis F. Stancato, email: stancato_louis@lilly.com Keywords: RAS, RAF, signaling pathways, colorectal cancer, xenograft models Received: September 28, 2016 Accepted: December 13, 2016 Published: December 16, 2016 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 BRAF mut melanoma, they have limited efficacy in BRAF mut CRC patients. In a RAS mut 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 BRAF mut and KRAS mut CRC cell lines through G1-cell cycle arrest. The anti-proliferative effects of LY3009120 in KRAS mut 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 BRAF mut and KRAS mut CRC xenograft models. Examination of potential resistance to LY3009120 demonstrated RAF-independent ERK and AKT activation in the KRAS mut CRC cell line HCT 116. These findings describe the preclinical activity of a panRAF inhibitor in a BRAF mut and KRAS mut CRC setting.
- Subjects :
- 0301 basic medicine
MAPK/ERK pathway
Time Factors
Colorectal cancer
Cell
Apoptosis
medicine.disease_cause
Extracellular Signal-Regulated MAP Kinases
Melanoma
Tumor Burden
medicine.anatomical_structure
Phenotype
Oncology
Female
RNA Interference
KRAS
Colorectal Neoplasms
HT29 Cells
Research Paper
Proto-Oncogene Proteins B-raf
congenital, hereditary, and neonatal diseases and abnormalities
colorectal cancer
Antineoplastic Agents
Transfection
Proto-Oncogene Proteins A-raf
Proto-Oncogene Proteins p21(ras)
03 medical and health sciences
Rats, Nude
medicine
Animals
Humans
Genetic Predisposition to Disease
Kinase activity
Protein kinase B
neoplasms
Protein Kinase Inhibitors
Cell Proliferation
Dose-Response Relationship, Drug
business.industry
Phenylurea Compounds
RAF
medicine.disease
HCT116 Cells
G1 Phase Cell Cycle Checkpoints
digestive system diseases
signaling pathways
Proto-Oncogene Proteins c-raf
030104 developmental biology
Pyrimidines
Immunology
Mutation
Cancer research
xenograft models
ARAF
business
Proto-Oncogene Proteins c-akt
RAS
Subjects
Details
- Language :
- English
- ISSN :
- 19492553
- Volume :
- 8
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Oncotarget
- Accession number :
- edsair.doi.dedup.....f9dee6fe3b13bc87210e961795693e6c