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 2

Depletion of ABL1 and ABL2 suppresses non–small cell lung carcinoma metastasis.

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Depletion of ABL1 and ABL2 suppresses non–small cell lung carcinoma meta...
(A) PC9 cells labeled with luciferase were transduced with lentiviruses encoding either scrambled (SCR) or ABL1/ABL2-specific (AA) shRNAs, and cells were delivered by intracardiac injection into nude mice. Tumor metastasis was detected by bioluminescent imaging (BLI). Representative images at day 28 are shown. (B) BLI counts (in photons per second [p/s]) of each individual mouse for the indicated groups (SCR n = 11, AA n = 15). (C) Percentage of mice surviving over the indicated times (days). (D) Depletion of ABL1 and ABL2 proteins was confirmed by Western blotting. (E) Luciferase-labeled H460 cells transduced with either SCR or AA shRNAs were delivered by intracardiac injection into nude mice. Representative metastasis images at day 12 are shown. (F) BLI counts of each mouse for the indicated groups (SCR n = 6, AA n = 9). (G) M4M5 cells transduced with either SCR or AA shRNAs were intracardiac injected into nude mice. Representative metastasis images at day 14 are shown. (H) BLI counts of each mouse for the indicated groups (n = 8 for each group). (I) Depletion of ABL1 and ABL2 proteins in H460 and M4M5 cells was confirmed by Western blotting. Data are represented as mean ± SEM. All P values were determined by Student’s t test or log-rank test.