C-Raf Is Required for the Initiation of Lung Cancer by K-Ras

Ras effectors required for transformation depend on the species, the cell type, and the tumor stage. However, these findings may be confounded because they were mainly conducted in cultured cells and by using H-Ras, the least commonly mutated Ras gene, to transform cells. K-Ras is the predominantly mutated Ras family member, and activating mutations in K-Ras are associated primarily with malignancies of the lung, pancreas, and colon. An in vivo evaluation of the role of Ras effectors in these cancer types is limited and has only been studied in the lung thus far. For example, the importance of the Ras/Rac axis has been validated in a K-Ras–mutant mouse model of lung cancer using conditional Rac knockout mice. Rac deficiency strongly impaired Ras tumorigenesis in the lung and developing tumors invariably retained wild-type Rac ( 7 ), suggesting an essential contribution of Rac to K-Ras G12D – initiated lung cancer. In addition, the Ras/phosphoinositide 3-kinase (PI3K)/AKT pathway has been demonstrated to be critical for Ras-mediated tumorigenesis. Mice expressing a Ras-binding–deficient form of the p110α subunit of PI3K were insensitive to oncogenic K-Ras–driven lung tumorigenesis ( 8 ). However, the contribution of the Ras/MAPK (mitogenactivated protein kinase) axis, a critical regulatory pathway that is often perturbed in cancer, to K-Ras–mediated transformation has been insufficiently addressed. The potential RESEARCH BRIEF doi: 10.1158/2159-8290.CD-10-0044 Authors’ Affiliations: 1 Li Ka Shing Centre, Cambridge Research Institute, Cancer Research UK, Cambridge, United Kingdom; 2 Max F. Perutz Laboratories, University of Vienna, Vienna, Austria; Divisions of 3 Genetics and 4 Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts Corresponding Author: David A Tuveson, Li Ka Shing Centre, Cambridge Research Institute, Cancer Research UK, Robinson Way, Cambridge CB2 0RE, United Kingdom. Phone: 44 (0)1223 404300; Fax: 44 (0)1223 404199; E-mail: [email protected] ©2011 American Association for Cancer Research. INTRODUCTION Activating mutations in Ras genes are observed in approximately 30% of human cancers ( 1 ). Ras stimulates multiple downstream effector pathways, which are constitutively activated in a growth factor–independent fashion in cancer cells expressing oncogenic Ras ( 2 ). Despite extensive efforts, targeted therapies against Ras were largely unsuccessful in clinical trials ( 3 ), and thus pharmacological inhibition of Ras effector pathways may represent a more feasible approach to eradicate Ras-mutant cancers. The contribution of Ras effector pathways to Rasmediated transformation has been studied in detail in human and murine cells ( 4–6 ). These studies found that the Note: Supplementary data for this article are available at Cancer Discovery Online (http://www.cancerdiscovery.aacrjournals.org). Cancer Discovery; Published OnlineFirst on June 30, 2011 as doi:10.1158/2159-8290.CD-10-0044 Copyright 2011 American Association for Cancer Research. Research. on June 18, 2017. © 2011 American Association for Cancer cancerdiscovery.aacrjournals.org Downloaded from Published OnlineFirst May 11, 2011; DOI: 10.1158/2159-8290.CD-10-0044