Targeting adhesion signaling in KRAS, LKB1 mutant lung adenocarcinoma.

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.

• Authors: Melissa Gilbert-Ross, Jessica Konen, Junghui Koo, John Shupe, Brian S Robinson, Walter Guy Wiles 4th, 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
• Journal: JCI insight (JCI Insight) Vol. 2 Issue 5 Pg. e90487 (03 09 2017) ISSN: 2379-3708 [Print] United States
• PMID: 28289710 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• KRAS protein, human
• Protein Kinase Inhibitors
• Focal Adhesion Protein-Tyrosine Kinases
• Protein Serine-Threonine Kinases
• STK11 protein, human
• AMP-Activated Protein Kinase Kinases
• Proto-Oncogene Proteins p21(ras)

Topics

• AMP-Activated Protein Kinase Kinases
• Adenocarcinoma (genetics)
• Animals
• Enzyme Activation
• Focal Adhesion Protein-Tyrosine Kinases (antagonists & inhibitors, metabolism)
• Humans
• Lung Neoplasms (genetics)
• Mice
• Mutation
• Protein Kinase Inhibitors (pharmacology)
• Protein Serine-Threonine Kinases (genetics, metabolism)
• Proto-Oncogene Proteins p21(ras) (genetics)
• Signal Transduction