Cancer Discov. 2013 Apr;3(4):444-57.

RHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas.

Konstantinidou G, Ramadori G, Torti F, Kangasniemi K, Ramirez RE, Cai Y, Behrens C, Dellinger MT, Brekken RA, Wistuba II, Heguy A, Teruya-Feldstein J, Scaglioni PP.

Department of Internal Medicine, Simmons Cancer Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.



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-specific targeted therapies using FAK inhibitors in patients with cancer.


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 purpose.

PMID: 23358651



Lung cancer is the leading cause of cancer worldwide and one of the most difficult cancer to treat due to its resistance to conventional treatment modalities. Additionally, late diagnosis may contribute to the insufficient tumor response to current treatments.

Lung cancer commonly displays a number of recurrent genetic abnormalities, such as mutations of KRAS or epidermal growth factor receptor (EGFR), which predict biological behavior or response to EGFR targeted therapy. These observations raise the hypothesis that the genotype of cancer cells not only determines their phenotype, but also defines their specific vulnerabilities. However, due to the incomplete knowledge of the cellular networks required for the maintenance of established tumors, there is a limited set of targeted cancer therapies available for clinical practice and only a small fraction of cancer patients can benefit from them. As a result, the vast majority of patients receive chemotherapies that are limited in their efficacy and often cause significant toxicity.

The goal of our study was to identify cellular networks that represent novel vulnerabilities of mutant KRAS-driven lung cancer that not only can be exploited for cancer therapy, but also can serve as biomarkers to identify patients that may benefit from such targeted therapies.

To achieve these goals, we dissected the mutant KRAS signaling pathways implicated in lung cancer progression. We took advantage of a genetically engineered mutant KRAS lung cancer mouse model combined with deficiency of the INK4a/ARF tumor suppressor, which undergoes two-hit inactivation in about 50% of mutant KRAS lung cancers. INK4a/ARF is a regulator of cell cycle dependent kinases and of the p53 tumor suppressor.

We found that the activity ERK1/2, a downstream target of KRAS, is deregulated in high-grade INK4a/ARF deficient tumors. INK4a/ARF inactivation has been previously found to cooperate with mutant KRAS to drive tumorigenesis. These results suggest that INK4a/ARF restrains the activation of ERK1/2 to limit cancer progression. To test this hypothesis we determined the function of ERK1/2 in mutant KRAS lung tumorigenesis. We found that in KRAS;INK4a/ARF deficient lung cancer, the small GTPase RHOA is highly activated and its silencing causes the death of lung cancer cells. With mechanistic experiments we determined that RHOA activation is due to ERK1/2-dependent inhibition of p190RHOGAP a GTP activating protein for RHOA.

Since RHOA is not druggable, we identified focal adhesion kinase (FAK) as the major downstream target of RHOA responsible for promoting the survival of cancer cells. Indeed, inhibition of FAK either by RNAi or pharmacological inhibitors recapitulates the effects of RHOA inhibition, resulting in selective apoptotic effects specifically in mutant KRAS;INK4a/ARF deficient lung cancer cells, and less pronounced but still significant apoptotic effects in mutant KRAS;p53 deficient lung cancer cells. FAK inhibition results in major cytoskeleton changes in vitro and induction of adenocarcinoma regression in a mouse model of mutant KRAS lung cancer in vivo.

These findings identify a novel, genotype-specific vulnerability of cancer cells, providing novel insights into the mechanisms that underlie oncogene addiction. Accordingly, clinical trials assessing the effect of pharmacologic inhibition of FAK are in progress in mutant KRAS lung cancer patients using INK4a/ARF or p53 status as an enrolment biomarker (National Cancer Institute Identifier: NCT01951690).


This study was supported by grants from NIH K08 CA112325, R01CA137195, American Cancer Society Institutional Research Grant #02-196, the Concern Foundation, the Gibson Foundation, Leukemia Texas Inc. (to P.P. Scaglioni), Cancer Prevention and Research Institute of Texas RP101496 (to G. Konstantinidou), Department of Defense (to M.T. Dellinger), American Heart Association (to G. Ramadori), Department of Defense W81XWH-07-1-0306, and Specialized Program of Research Excellence in Lung Cancer P50CA70907 (to I.I. Wistuba). In vivo imaging studies were made possible by the UT Southwestern small animal imaging resource, supported in part by grants NCI U24 CA126608, NIH BTRP P41-RR02584, and the Harold C. Simmons Cancer Center through NCI Cancer Center support grant 1P30 CA 142543-01.

Pier Paolo Scaglioni picture1

Proposed model of ERK-RHOA-FAK regulation in NSCLC. In INK4a/ARF or p53 deficient lung cancer cells, mutant KRAS expression leads to sustained activation of ERK1/2, inactivation of p190RHOGAP and unremitting RHOA-FAK signaling, which is essential for the maintenance high-grade lung cancer. Thus, this signaling network is the Achilles heel of high-grade lung tumors. The sites of possible therapeutic intervention are indicated and lead to tumor cell death (dashed line). Orange and green color denotes impaired and activated signaling respectively.

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