Journal
CANCER DISCOVERY
Volume 3, Issue 4, Pages 444-457Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-12-0388
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Funding
- NIH [K08 CA 112325, R01CA137195]
- American Cancer Society Institutional Research [02-196]
- Concern Foundation
- Gibson Foundation
- Leukemia Texas Inc.
- Cancer Prevention and Research Institute of Texas [RP101496]
- American Heart Association
- Department of Defense [W81XWH-07-1-0306]
- Specialized Program of Research Excellence in Lung Cancer [P50CA70907]
- NCI [U24 CA126608]
- NIH BTRP [P41-RR02584]
- Harold C. Simmons Cancer Center through NCI Cancer Center [1P30 CA 142543-01]
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Non-small cell lung cancer (NSCLC) often expresses mutant KRAS together with tumor-associated mutations of the CDKN2A locus, which are associated with aggressive, therapy-resistant tumors. Here, we unravel specific requirements for the maintenance of NSCLC that carries this genotype. We establish that the extracellular signal-regulated kinase (ERK)/RHOA/focal adhesion kinase (FAK) network is deregulated in high-grade lung tumors. Suppression of RHOA or FAK induces cell death selectively in mutant KRAS;INK4A/ARF-deficient lung cancer cells. Furthermore, pharmacologic inhibition of FAK caused tumor regression specifically in the high-grade lung cancer that developed in mutant Kras;Cdkn2a-null mice. These findings provide a rationale for the rapid implementation of genotype-specifi c targeted therapies using FAK inhibitors in patients with cancer. SIGNIFICANCE: Targeted therapies are effective for only a small fraction of patients with cancer. We report that FAK inhibitors exert potent antitumor effects in NSCLCs that express mutant KRAS in association with INK4A/ARF deficiency. These results reveal a novel genotype-specific vulnerability of cancer cells that can be exploited for therapeutic purposes. (C) 2013 AACR.
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