Department of Hematology and Medical Oncology, Emory University School of Medicine.
Winship Cancer Institute of Emory University.
JCI Insight. 2017 Mar 9;2(5):e90487. doi: 10.1172/jci.insight.90487.
Loss of LKB1 activity is prevalent in 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 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 and mutant genetically engineered mouse model () 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 , but not , was sufficient to drive collective invasion and collagen alignment that was highly sensitive to FAK inhibition. Treatment of early, stage-matched 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 and comutated human lung adenocarcinoma patients. Our results suggest that patients with mutant tumors should be stratified for early treatment with FAK inhibitors.
LKB1 活性缺失在 突变型肺腺癌中普遍存在，并促进侵袭性和耐药性肿瘤的发生。先前的研究表明，LKB1 是黏着斑激酶 (FAK) 的负调控因子，但缺乏体内研究来验证 FAK 抑制在 突变型癌症中的疗效。在这里，我们采用药理学方法证明 FAK 抑制是这种高风险分子亚型的有效早期治疗策略。我们建立了一个 lenti-Cre 诱导的 和 突变的基因工程小鼠模型 ()，该模型发展为 100%的肺腺癌，并表明在被高水平胶原包围的集体浸润细胞中，FAK 激活具有高时空特异性。在 3D 中模拟侵袭时，缺失 ，而不是 ，足以驱动集体浸润和胶原排列，对 FAK 抑制高度敏感。用 FAK 抑制剂单药治疗早期、匹配阶段的 肿瘤，对肿瘤进展、侵袭和肿瘤相关胶原有显著影响。慢性治疗延长了生存时间，并阻碍了局部淋巴结转移。最后，我们在 和 共突变的人类肺腺癌患者中发现了局灶性上调的 FAK 和与胶原相关的集体浸润。我们的结果表明，应根据 FAK 抑制剂对 突变型肿瘤患者进行分层，以进行早期治疗。
