Targeting adhesion signaling in <i>KRAS, LKB1</i> mutant lung adenocarcinoma.

Abstract

Loss of LKB1 activity is prevalent in <i>KRAS</i> 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 <i>LKB1</i> 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 <i>Kras</i> and <i>Lkb1</i> mutant genetically engineered mouse model (<i>KL</i>_Lenti) 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 <i>Lkb1</i>, but not <i>p53</i>, was sufficient to drive collective invasion and collagen alignment that was highly sensitive to FAK inhibition. Treatment of early, stage-matched <i>KL</i>_Lenti 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 <i>KRAS</i> and <i>LKB1</i> comutated human lung adenocarcinoma patients. Our results suggest that patients with <i>LKB1</i> mutant tumors should be stratified for early treatment with FAK inhibitors.