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Expression Of LKB1 Tumor Suppressor Determines Sensitivity To 2-deoxyglucose In NSCLC
L. J. Inge, K. D. Coon, E. E. Cwengros, M. A. Smith, R. M. Bremner*. Heart and Lung Institute, Thoracic Oncology Division, St. Joseph's Hospital and Medical Center, Phoenix, AZ,
Background:
Targeted small molecule therapy holds promise to improve the outcomes for patients with NSCLC. However, as illustrated by the EGFR-receptor inhibitors, certain sub-populations of NSCLC patients with distinct molecular characteristics appear to benefit more from targeted therapies than others. Such distinct characteristics (biomarkers) can be utilized to direct targeted therapy towards patients who are most likely to respond, thus optimizing benefit and personalizing therapy. A novel agent with significant anti-neoplastic potential now entering phase 1 trials is the glucose analog, 2-deoxyglucose (2-DG). 2-DG preferentially targets tumor cells due to their increased glucose uptake. Mechanistically, 2-DG inhibits cellular metabolism and induces energetic stress, resulting in decreased cellular viability. The serine-threonine kinase, LKB1 regulates cellular metabolism and may play an important role in 2-DG induced cellular damage. Energetic stress activates LKB1 and induces cell cycle arrest as a means to conserve energy. Conversely, cells that lack LKB1 fail to react to such stress and undergo cell death. Somatic loss of LKB1 has been found to occur in 30% of NSCLC, potentially indicating increased cellular susceptibility to 2-DG therapy in LKB1 null patients. We hypothesized that loss of LKB1 would increase sensitivity to 2-DG treatment, and that LKB1 expression has the potential to be used as a biomarker to direct therapy in patients with NSCLC.
Methods:
LKB1 negative (H23, H2122) and positive (H2009, H441) NSCLC cell lines were treated with decreasing doses of 2-deoxyglucose (2-DG) for 72 hours. Cell viability, markers of apoptosis (e.g. PARP, Caspases), and gene expression profiles were evaluated from treated versus untreated samples.
Results:
LKB1 negative NSCLC cell lines (Fig. 1A) treated with 2-DG displayed a significant decrease in cell viability (even at low doses; P=5.73*10-13) compared to LKB1 positive NSCLC cell lines (Fig. 1B). 2-DG treatment induced apoptosis in LKB1 negative cell lines, but not in LKB1 positive cells (Fig. 1C). Gene expression profiles of 2-DG treated cells revealed an increase in the expression of pro-apoptotic markers in LKB negative cell lines, while LKB1 positive lines demonstrated no changes in expression.
Conclusions:
2-DG therapy has the potential to be a useful agent in the treatment of patients with NSCLC. Loss of LKB1 is associated with a marked increase in susceptibility to 2-DG treatment in NSCLC lines, even at low doses. Determination of LKB1 status may help direct therapy to those patients most likely to benefit from this novel approach. 
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