title: Inactivation of ABL kinases suppresses non-small cell lung cancer metastasis.
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 ofABL1,ABL2, 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.
authors.affiliation: Department of Pharmacology and Cancer Biology.
authors.forename: Jing Jin
authors.initials: JJ
authors.lastname: Gu
authors.affiliation: Division of Laboratory Animal Resources.
authors.forename: Clay
authors.initials: C
authors.lastname: Rouse
authors.affiliation: Department of Pharmacology and Cancer Biology.
authors.forename: Xia
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Pharmacology and Cancer Biology.
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Surgery, Duke University School of Medicine, Durham, North Carolina, USA.|Department of Surgery, University of California, San Diego, San Diego, California, USA.
authors.forename: Mark W
authors.initials: MW
authors.lastname: Onaitis
authors.affiliation: Department of Pharmacology and Cancer Biology.
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Pendergast