Targeting adhesion signaling in KRAS, LKB1 mutant lung adenocarcinoma

• DOI: 10.1172/jci.insight.90487
• Publication Date: 2017-03-08T16:01:03Z
• Authors: Melissa Gilbert-Ross; Jessica Konen; Junghui Koo; John Shupe; Brian S. Robinson; Walter Guy Wiles; Chunzi Huang; W. David Martin; Madhusmita Behera; Geoffrey H. Smith; Charles E. Hill; Michael R. Rossi; Gabriel L. Sica; Manali Rupji; Zhengjia Chen; Jeanne Kowalski; Andrea L. Kasinski; Suresh S. Ramalingam; Haian Fu; Fadlo R. Khuri; Wei Zhou; Adam I. Marcus
• Keywords: 0303 health sciences; Lung Neoplasms; Adenocarcinoma; Protein Serine-Threonine Kinases; 3. Good health; Enzyme Activation; Proto-Oncogene Proteins p21(ras); Mice; 03 medical and health sciences; AMP-Activated Protein Kinase Kinases; Focal Adhesion Protein-Tyrosine Kinases; Mutation; Animals; Humans; Protein Kinase Inhibitors; Signal Transduction

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