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Published on: July 21, 2018
Expression of LKB1 tumor suppressor in non-small cell lung cancer determines sensitivity to 2-deoxyglucose
Landon J Inge1, Keith D Coon, Michael A Smith
1Center for Thoracic Disease, Heart and Lung Institute, St Joseph's Hospital and Medical Center, Phoenix, Arizona 85013, USA.
Objective:
Targeted therapy promises to improve patient outcome in non-small cell lung cancer. Biomarkers can direct targeted therapy toward patients who are most likely to respond, thus optimizing benefit. A novel agent with antineoplastic potential is the glucose analog, 2-deoxyglucose. 2-Deoxyglucose targets tumor cells, owing to their increased glucose uptake, inhibiting cellular metabolism and inducing energetic stress, resulting in decreased cellular viability. The tumor suppressor LKB1 is activated by energetic stress, and cells that lack LKB1 fail to respond and undergo cell death, suggesting that LKB1-null non-small cell lung cancer may have an increased susceptibility to 2-deoxyglucose. Inasmuch as somatic loss of LKB1 is a frequent event in non-small cell lung cancer, LKB1 expression could be used as a biomarker for directing 2-deoxyglucose therapy in patients with this type of cancer.
Methods:
LKB1-positive and LKB1-negative non-small cell lung cancer cell lines were evaluated for cell viability, markers of apoptosis, and gene expression after 2-deoxyglucose treatment and compared with vehicle control.
Results:
LKB1-negative cells treated with 2-deoxyglucose displayed a significant decrease in cell viability compared with LKB1-positive cells. Gene expression profiles of 2-deoxyglucose treated cells revealed changes in apoptotic markers in LKB1-negative cells, correlating with activation of apoptosis. Re-expression of LKB1 prevented 2-deoxyglucose mediated apoptosis, demonstrating the critical role of LKB1 in mediating 2-deoxyglucose toxicity.
Conclusions:
LKB1 loss increases susceptibility to 2-deoxyglucose treatment in non-small cell lung cancer lines, even at low doses. Thus, determination of LKB1 status may help direct therapy to those patients most likely to benefit from this novel approach, making it useful in the treatment of patients with non-small cell lung cancer.
Insights
Loss of LKB1 in non-small cell lung cancer increases susceptibility to 2-deoxyglucose, a novel targeted therapy. LKB1 status can guide treatment for patients most likely to benefit from 2-deoxyglucose.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Targeted therapy in non-small cell lung cancer (NSCLC) aims to improve patient outcomes.
- Biomarkers are crucial for directing targeted therapies to responsive patient populations.
- 2-deoxyglucose (2-DG), a glucose analog, exhibits antineoplastic potential by inhibiting tumor cell metabolism.
Purpose of the Study:
- To investigate the role of Liver Kinase B1 (LKB1) status in NSCLC response to 2-deoxyglucose.
- To determine if LKB1-null NSCLC exhibits increased susceptibility to 2-DG.
- To evaluate LKB1 as a potential biomarker for 2-DG therapy in NSCLC.
Main Methods:
- Cultured LKB1-positive and LKB1-negative NSCLC cell lines.
- Treated cell lines with 2-deoxyglucose or vehicle control.
- Assessed cell viability, apoptosis markers, and gene expression profiles.
Main Results:
- LKB1-negative NSCLC cells showed significantly reduced viability upon 2-DG treatment compared to LKB1-positive cells.
- 2-DG treatment induced apoptosis in LKB1-negative cells, evidenced by changes in apoptotic markers.
- Re-expression of LKB1 abolished 2-DG-induced apoptosis, confirming LKB1's role in 2-DG toxicity.
Conclusions:
- LKB1 loss enhances NSCLC sensitivity to 2-deoxyglucose, even at low concentrations.
- LKB1 expression status can serve as a predictive biomarker for 2-DG therapy.
- Determining LKB1 status may optimize treatment selection for NSCLC patients receiving 2-DG.