Oncotarget

Research Papers:

LY3009120, a panRAF inhibitor, has significant anti-tumor activity in BRAF and KRAS mutant preclinical models of colorectal cancer

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 and Louis F. Stancato _

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Oncotarget. 2017; 8:9251-9266. https://doi.org/10.18632/oncotarget.14002

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Abstract

Eliza Vakana1,*, Susan Pratt1,*, Wayne Blosser1, Michele Dowless1, Nicholas Simpson2, Xiu-Juan Yuan3, Susan Jaken3, Jason Manro4, Jennifer Stephens1, Youyan Zhang1, Lysiane Huber1, Sheng-Bin Peng1, Louis F. Stancato1

1Oncology Discovery Research, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA

2Discovery Research, Advanced Testing Laboratory, Cincinnati, OH 45242, USA

3Cell Technologies, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA

4Discovery 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 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.


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