@article{10.1172/jci.insight.90487, author = {Melissa Gilbert-Ross AND Jessica Konen AND Junghui Koo AND John Shupe AND Brian S. Robinson AND Walter Guy Wiles IV AND Chunzi Huang AND W. David Martin AND Madhusmita Behera AND Geoffrey H. Smith AND Charles E. Hill AND Michael R. Rossi AND Gabriel L. Sica AND Manali Rupji AND Zhengjia Chen AND Jeanne Kowalski AND Andrea L. Kasinski AND Suresh S. Ramalingam AND Haian Fu AND Fadlo R. Khuri AND Wei Zhou AND Adam I. Marcus}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {Targeting adhesion signaling in KRAS, LKB1 mutant lung adenocarcinoma}, year = {2017}, month = {3}, volume = {2}, url = {https://insight.jci.org/articles/view/90487}, 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.}, number = {5}, doi = {10.1172/jci.insight.90487}, url = {https://doi.org/10.1172/jci.insight.90487}, }