RHOA-FAK is a required signaling axis for the maintenance of KRAS-driven lung adenocarcinomas
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Abstract
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. 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. Cancer Discov; 3(4); 444–57. ©2013 AACR. This article is highlighted in the In This Issue feature, p. 363
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RHO/ROCK signaling can promote YAP activation, and Rhoa is required for mutant Kras-induced NSCLC in mice.
“RHO/ROCK signaling can promote YAP activation; also, Rhoa is required for mutant Kras-induced NSCLC in mice (42).”
From Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy (2023) · cites this paper as [42]
RHOA is required for Kras G12D-driven lung adenocarcinoma.
“and for Kras G12D -driven lung adenocarcinoma (42)”
From Genome-Wide CRISPR Screens Identify Multiple Synthetic Lethal Targets That Enhance KRASG12C Inhibitor Efficacy (2023) · cites this paper as [42]
FAK acts downstream of KRAS, and its inhibition is effective in suppressing the progression of KRAS mutant cancer.
“FAK acts downstream of KRAS, and its inhibition is effective in suppressing the progression of KRAS mutant cancer.[ 12, 13, 14 ]”
From Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK–YAP Signaling (2021) · cites this paper as [14]
FAK is a downstream signaling component of KRAS.
“First, FAK is a downstream signaling component of KRAS, emphasizing its directly linked function in supporting the KRAS activity.[ 14, 42 ]”
From Focal Adhesion Kinase (FAK) Inhibition Synergizes with KRAS G12C Inhibitors in Treating Cancer through the Regulation of the FAK–YAP Signaling (2021) · cites this paper as [14]
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- Authors
- Konstantinidou, G., Ramadori, G., Torti, F., Kangasniemi, K., Ramirez, R. E., Cai, Y., Behrens, C., Dellinger, M. T., Brekken, R. A., Wistuba, I. I., Heguy, A., Teruya-Feldstein, J., & Scaglioni, P. P.
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- Authors' Affiliations: 1Department of Internal Medicine, Simmons Cancer Center; 2Department of Internal Medicine, Division of Hypothalamic Research; 3Department of Surgery, Hamon Center for Therapeutic Oncology Research, and 4Advanced Imaging Research Center, The University of Texas Southwestern Medical Center, Dallas; Departments of 5Pathology, 6Thoracic/Head and Neck Medical Oncology, and 7Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas; 8Human Oncology and Pathogenesis Program and 9Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York
- Corresponding author
- Scaglioni, Pier Paolo
- ORCID
- Venue
- Cancer Discovery
- Published
- 2013-04-01
- Volume
- 3
- Issue
- 4
- Pages
- 444-457
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC3625467
- OpenAlex
- W2109788976
- Cited by
- 114
- References
- 46
- Citations by year
- 2026: 6 · 2025: 1 · 2024: 3 · 2023: 6 · 2022: 9 · 2021: 9 · 2020: 12 · 2019: 9 · 2018: 10 · 2017: 13 · 2016: 11 · 2015: 17 · 2014: 7 · 2013: 1
- FWCI
- 5.34
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- BORIS (University Library Bern) (submittedVersion)
- Funders
- National Cancer Institute (R01CA137195, NCI U24 CA126608, P50CA070907, K08CA112325, NIH K08 CA 112325, U24CA126608, P30CA008748, P30CA142543)
- National Center for Research Resources (P41RR002584, NIH BTRPP41-RR02584)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Keywords
- RhoA, focal adhesion kinase, KRAS mutation, non-small cell lung cancer, lung adenocarcinoma, CDKN2A, ERK signaling, FAK inhibitors, tumor regression, cancer cell death
- MeSH terms
- Adenocarcinoma of Lung, Adenocarcinoma, Animals, Carcinoma, Non-Small-Cell Lung, Female, Humans, Lung Neoplasms, Mice, Nude, Mice, Transgenic, Genes, ras, Signal Transduction, rhoA GTP-Binding Protein, Xenograft Model Antitumor Assays, Cell Line, Tumor, Protein Kinase Inhibitors, Extracellular Signal-Regulated MAP Kinases, Mice, Focal Adhesion Protein-Tyrosine Kinases
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