Gu Jing Jin, Rouse Clay, Xu Xia, Wang Jun, Onaitis Mark W, Pendergast Ann Marie
Department of Pharmacology and Cancer Biology.
Division of Laboratory Animal Resources.
JCI Insight. 2016 Dec 22;1(21):e89647. doi: 10.1172/jci.insight.89647.
Current therapies to treat non-small cell lung carcinoma (NSCLC) have proven ineffective owing to transient, variable, and incomplete responses. Here we show that ABL kinases, ABL1 and ABL2, promote metastasis of lung cancer cells harboring EGFR or KRAS mutations. Inactivation of ABL kinases suppresses NSCLC metastasis to brain and bone, and other organs. ABL kinases are required for expression of prometastasis genes. Notably, ABL1 and ABL2 depletion impairs extravasation of lung adenocarcinoma cells into the lung parenchyma. We found that ABL-mediated activation of the TAZ and β-catenin transcriptional coactivators is required for NSCLC metastasis. ABL kinases activate TAZ and β-catenin by decreasing their interaction with the β-TrCP ubiquitin ligase, leading to increased protein stability. High-level expression of , , and a subset of ABL-dependent TAZ- and β-catenin-target genes correlates with shortened survival of lung adenocarcinoma patients. Thus, ABL-specific allosteric inhibitors might be effective to treat metastatic lung cancer with an activated ABL pathway signature.
目前用于治疗非小细胞肺癌（NSCLC）的疗法已被证明无效，因为其反应短暂、多变且不完全。在此我们表明，ABL激酶ABL1和ABL2促进携带EGFR或KRAS突变的肺癌细胞转移。ABL激酶的失活可抑制NSCLC向脑、骨及其他器官的转移。ABL激酶是转移促进基因表达所必需的。值得注意的是，ABL1和ABL2的缺失会损害肺腺癌细胞向肺实质的外渗。我们发现，NSCLC转移需要ABL介导的TAZ和β-连环蛋白转录共激活因子的激活。ABL激酶通过减少TAZ和β-连环蛋白与β-TrCP泛素连接酶的相互作用来激活它们，从而导致蛋白质稳定性增加。TAZ、β-连环蛋白以及一部分ABL依赖性TAZ和β-连环蛋白靶基因的高表达与肺腺癌患者的生存期缩短相关。因此，ABL特异性变构抑制剂可能对治疗具有激活ABL途径特征的转移性肺癌有效。
