Inactivation of ABL kinases suppresses non-small cell lung cancer metastasis
Jing Jin Gu1, Clay Rouse2, Xia Xu1
1Department of Pharmacology and Cancer Biology.
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.
Insights
ABL kinases (ABL1 and ABL2) drive non-small cell lung carcinoma (NSCLC) metastasis by activating TAZ and β-catenin. Inhibiting these kinases may treat advanced NSCLC.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis
Background:
- Current non-small cell lung carcinoma (NSCLC) therapies show limited efficacy due to variable patient responses.
- Metastasis remains a primary cause of mortality in NSCLC patients, necessitating novel therapeutic targets.
Purpose of the Study:
- To investigate the role of ABL kinases (ABL1 and ABL2) in promoting NSCLC metastasis.
- To identify the molecular mechanisms by which ABL kinases contribute to cancer cell dissemination.
Main Methods:
- Utilized genetic depletion of ABL1 and ABL2 in NSCLC models.
- Assessed the impact on metastasis to various organs, including brain and bone.
- Investigated the regulation of TAZ and β-catenin transcriptional coactivators by ABL kinases.
Main Results:
- ABL1 and ABL2 were found to promote metastasis in NSCLC cells with EGFR or KRAS mutations.
- Inactivation of ABL kinases significantly suppressed NSCLC metastasis and impaired cancer cell extravasation.
- ABL kinase activity was essential for TAZ and β-catenin activation via reduced interaction with β-TrCP ubiquitin ligase, enhancing protein stability.
Conclusions:
- ABL kinases are critical drivers of NSCLC metastasis.
- Targeting ABL kinases, potentially with allosteric inhibitors, offers a promising therapeutic strategy for metastatic NSCLC, particularly in tumors with an activated ABL pathway signature.
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