title: Targeting adhesion signaling inKRAS, LKB1mutant lung adenocarcinoma.
abstract: Loss of LKB1 activity is prevalent inKRASmutant 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 inLKB1mutant 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-inducedKrasandLkb1mutant 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 ofLkb1, but notp53, was sufficient to drive collective invasion and collagen alignment that was highly sensitive to FAK inhibition. Treatment of early, stage-matchedKLLentitumors 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 inKRASandLKB1comutated human lung adenocarcinoma patients. Our results suggest that patients withLKB1mutant tumors should be stratified for early treatment with FAK inhibitors.
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine.|Winship Cancer Institute of Emory University.
authors.forename: Melissa
authors.initials: M
authors.lastname: Gilbert-Ross
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine.|Winship Cancer Institute of Emory University.
authors.forename: Jessica
authors.initials: J
authors.lastname: Konen
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine.|Winship Cancer Institute of Emory University.
authors.forename: Junghui
authors.initials: J
authors.lastname: Koo
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine.|Winship Cancer Institute of Emory University.
authors.forename: John
authors.initials: J
authors.lastname: Shupe
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Robinson
authors.affiliation: Winship Cancer Institute of Emory University.|The Cancer Animal Models Shared Resource.
authors.forename: Walter Guy
authors.initials: WG
authors.lastname: Wiles
authors.affiliation: Winship Cancer Institute of Emory University.|The Cancer Animal Models Shared Resource.
authors.forename: Chunzi
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine.
authors.forename: W David
authors.initials: WD
authors.lastname: Martin
authors.affiliation: Winship Research Informatics Shared Resource, Winship Cancer Institute.
authors.forename: Madhusmita
authors.initials: M
authors.lastname: Behera
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine.
authors.forename: Geoffrey H
authors.initials: GH
authors.lastname: Smith
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine.
authors.forename: Charles E
authors.initials: CE
authors.lastname: Hill
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine.|Department of Radiation Oncology, Emory University School of Medicine.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Rossi
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine.
authors.forename: Gabriel L
authors.initials: GL
authors.lastname: Sica
authors.affiliation: Winship Cancer Institute of Emory University.
authors.forename: Manali
authors.initials: M
authors.lastname: Rupji
authors.affiliation: Winship Cancer Institute of Emory University.|Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.
authors.forename: Zhengjia
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Winship Cancer Institute of Emory University.|Department of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.
authors.forename: Jeanne
authors.initials: J
authors.lastname: Kowalski
authors.affiliation: Department of Biological Sciences, Purdue University, West Lafayette, Indiana, USA.
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Kasinski
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine.|Winship Cancer Institute of Emory University.
authors.forename: Suresh S
authors.initials: SS
authors.lastname: Ramalingam
authors.affiliation: Winship Cancer Institute of Emory University.|Department of Pharmacology, Emory University School of Medicine.
authors.forename: Haian
authors.initials: H
authors.lastname: Fu
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine.|Winship Cancer Institute of Emory University.
authors.forename: Fadlo R
authors.initials: FR
authors.lastname: Khuri
authors.affiliation: 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.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhou
authors.affiliation: Department of Hematology and Medical Oncology, Emory University School of Medicine.|Winship Cancer Institute of Emory University.
authors.forename: Adam I
authors.initials: AI
authors.lastname: Marcus
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000230:Adenocarcinoma / Q000235:genetics*; D000818:Animals; D004789:Enzyme Activation; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics*; D051379:Mice; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D015398:Signal Transduction
chemical_list: C117307:KRAS protein, human; D047428:Protein Kinase Inhibitors; D051416:Focal Adhesion Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D016283:Proto-Oncogene Proteins p21(ras)