Inactivation of ABL kinases suppresses non–small cell lung cancer metastasis
Jing Jin Gu, Clay Rouse, Xia Xu, Jun Wang, Mark W. Onaitis, Ann Marie Pendergast
Jing Jin Gu, Clay Rouse, Xia Xu, Jun Wang, Mark W. Onaitis, Ann Marie Pendergast
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Research Article Cell biology Oncology

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 of ABL1, 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

Jing Jin Gu, Clay Rouse, Xia Xu, Jun Wang, Mark W. Onaitis, Ann Marie Pendergast

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Figure 3

Inhibition of ABL kinase activity suppresses non–small cell lung carcinoma metastasis.

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Inhibition of ABL kinase activity suppresses non–small cell lung carcino...
(A) PC9M cells labeled with luciferase were delivered by intracardiac injection into nude mice. Mice were treated 1 day after injection with or without GNF5 at 100 mg/kg by oral gavage twice per day. Representative images taken at day 18 are shown. (B) Bioluminescent imaging (BLI) counts (in photons per second [p/s]) of each mouse for the indicated groups (n = 6 each group). (C) M4M5 cells labeled with luciferase were delivered by intracardiac injection into nude mice. Mice were treated 8 days after injection with or without GNF5 at 50 mg/kg by intraperitoneal injection once per day. Representative images at 12 days after GNF5 treatment are shown. (D) BLI counts of each mouse for the indicated groups (control, n = 7, GNF5 n = 9). Data are represented as mean ± SEM. All P values were determined by Student’s t test. (E and F) Luciferase-labeled PC9M cells were delivered by intracardiac injection into nude mice. After 10 days, mice bearing metastatic tumors were divided into 2 groups, and treated with vehicle (E) or GNF5 (F) by oral gavage for 14 days. Representative BLI images (left); BLI counts of each individual mouse before and after treatment for the indicated groups (right). Control n = 4, GNF5 treated n = 7.