Inactivation of ABL Kinases Suppresses Non-small Cell Lung Cancer Metastasis

Overview

Journal JCI Insight

Specialties Biomedical Engineering
General Medicine

Date 2016 Dec 27

PMID 28018973

Citations 40

Authors

Jing Jin Gu

Clay Rouse

Xia Xu

Jun Wang

Mark W Onaitis

Ann Marie Pendergast

Affiliations

Soon will be listed here.

Abstract

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.

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