期刊
JCI INSIGHT
卷 1, 期 21, 页码 -出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.89647
关键词
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资金
- P30 Cancer Center [P30 CA014236]
- NIH [R01 CA195549, R21 CA201486]
- Free to Breathe Metastasis Research Grant
- Uniting Against Lung Cancer Grant
- AATS Graham Foundation Research Grant
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 beta-catenin transcriptional coactivators is required for NSCLC metastasis. ABL kinases activate TAZ and beta-catenin by decreasing their interaction with the beta-TrCP ubiquitin ligase, leading to increased protein stability. High-level expression of ABL1, ABL2, and a subset of ABL-dependent TAZ- and beta-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.
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