Format

Send to

Choose Destination
JCI Insight. 2017 Mar 9;2(5):e90487. doi: 10.1172/jci.insight.90487.

Targeting adhesion signaling in KRAS, LKB1 mutant lung adenocarcinoma.

Author information

1
Department of Hematology and Medical Oncology, Emory University School of Medicine,; Winship Cancer Institute of Emory University.
2
Department of Pathology and Laboratory Medicine, Emory University School of Medicine.
3
Winship Cancer Institute of Emory University,; The Cancer Animal Models Shared Resource.
4
Department of Hematology and Medical Oncology, Emory University School of Medicine.
5
Winship Research Informatics Shared Resource, Winship Cancer Institute.
6
Department of Pathology and Laboratory Medicine, Emory University School of Medicine,; Department of Radiation Oncology, Emory University School of Medicine.
7
Winship Cancer Institute of Emory University.
8
Winship Cancer Institute of Emory University,; Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.
9
Department of Biological Sciences, Purdue University, West Lafayette, Indiana, USA.
10
Department of Pharmacology, Emory University School of Medicine,; Winship Cancer Institute of Emory University.
11
Department of Hematology and Medical Oncology, Emory University School of Medicine,; Winship Cancer Institute of Emory University,; Department of Pathology and Laboratory Medicine, Emory University School of Medicine,; Department of Human Genetics, Emory University, Atlanta, Georgia, USA.

Abstract

Loss of LKB1 activity is prevalent in KRAS mutant lung adenocarcinoma and promotes aggressive and treatment-resistant tumors. Previous studies have shown that LKB1 is a negative regulator of the focal adhesion kinase (FAK), but in vivo studies testing the efficacy of FAK inhibition in LKB1 mutant cancers are lacking. Here, we took a pharmacologic approach to show that FAK inhibition is an effective early-treatment strategy for this high-risk molecular subtype. We established a lenti-Cre-induced Kras and Lkb1 mutant genetically engineered mouse model (KLLenti) that develops 100% lung adenocarcinoma and showed that high spatiotemporal FAK activation occurs in collective invasive cells that are surrounded by high levels of collagen. Modeling invasion in 3D, loss of Lkb1, but not p53, was sufficient to drive collective invasion and collagen alignment that was highly sensitive to FAK inhibition. Treatment of early, stage-matched KLLenti tumors with FAK inhibitor monotherapy resulted in a striking effect on tumor progression, invasion, and tumor-associated collagen. Chronic treatment extended survival and impeded local lymph node spread. Lastly, we identified focally upregulated FAK and collagen-associated collective invasion in KRAS and LKB1 comutated human lung adenocarcinoma patients. Our results suggest that patients with LKB1 mutant tumors should be stratified for early treatment with FAK inhibitors.

Supplemental Content

Full text links

Icon for American Society for Clinical Investigation Icon for PubMed Central
Loading ...
Support Center