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Y. Shyr



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    P3.05 - Poster Session 3 - Preclinical Models of Therapeutics/Imaging (ID 159)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Biology
    • Presentations: 1
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      P3.05-017 - LKB1 loss induces characteristic pathway activation in human tumors and confers sensitivity to MEK inhibition due to attenuated PI3K-AKT-FOXO3 signaling. (ID 2847)

      09:30 - 09:30  |  Author(s): Y. Shyr

      • Abstract

      Background
      Inactivation of STK11/LKB1 is one of the most common genetic events in lung cancer, and understanding the cellular phenotypes and molecular pathways altered as a consequence will aid the development of therapeutic strategies targeting LKB1-deficient cancers.

      Methods
      We report the comprehensive analysis of gene and protein expression patterns associated with LKB1 loss in lung adenocarcinomas, through which we identify hallmarks of altered tumor metabolism and down-regulation of the PI3K/AKT pathway.

      Results
      Significant differences are observed between human tumors and those derived from a genetically engineered mouse model of LKB1 loss. A 16-gene signature is predictive of both mutational and non-mutational LKB1 loss in human tumors. Cell lines expressing this signature show increased sensitivity to MEK inhibition, independent of mutations in RAS and RAF family members. Restoration of LKB1 in lung cancer cell lines down-regulates the gene expression pattern, attenuates FOXO3, and induces resistance to MEK inhibition.

      Conclusion
      These findings identify characteristic phenotypic features of LKB1-deficient tumors and identify LKB1 loss as a novel determinant of MEK sensitivity.

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    P3.20 - Poster Session 3 - Early Detection and Screening (ID 174)

    • Event: WCLC 2013
    • Type: Poster Session
    • Track: Imaging, Staging & Screening
    • Presentations: 1
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      P3.20-006 - Proteomic analysis of the bronchial epithelium to develop a molecular signature of risk for lung cancer (ID 2008)

      09:30 - 09:30  |  Author(s): Y. Shyr

      • Abstract

      Background
      A small percentage of at-risk individuals ultimately develop lung cancer. This warrants a search for a strategy to identify individuals who will be developing lung cancer. The bronchial epithelium represents the field of carcinogenesis and may serve as surrogate tissue for biomarker of risk. Therefore we hypothesized that proteomic alterations in the histologically normal airway epithelium from risk stratified individuals allow us to derive a signature of risk of developing lung cancer.

      Methods
      We have collected bronchial brushings specimens from risk stratified individuals (Bach PB et al. 2003) and categorized them as Control (group 1), low (group 2) and high (group 3) risk groups. We collected three bronchial brushings specimens from each individual in a single session for acquiring shotgun proteomics (n=30). We also collected brushings from cancer patients whose risk criteria are similar to low (group 5) and high (group 6) risk groups as well as a group of never smoker lung cancer patients (group 4). Shotgun proteomics data were acquired from 3 technical replicates of pooled specimens from 5 individuals. Candidate biomarkers were selected based on group comparison and trend analysis.

      Results
      We have acquired shotgun proteomics data from bronchial brushings specimen from individuals at-risk for lung cancer development. A total of 4973 proteins have been identified. Jonchere-Terpestra trend test was performed among control, low risk and high risk groups (Groups 1, 2, and 3). Expression level of 316 proteins were altered (trend p <0.05) with 238 proteins demonstrating upward and 78 proteins downward trends. DNA repair and oxidative stress and the galactose metabolic enzyme pathway were enriched in the upward trend analysis.

      Conclusion
      We identified a proteomic candidate signature of risk of developing lung cancer from histologically normal bronchial epithelial cells. Integration of these results with those upcoming from two other molecular platforms will allow us to narrow down the molecular aberrations most predictive of risk. This signature will be validated in an independent cohort. Such signature of risk for lung cancer may serve as a powerful tool for lung cancer risk assessment and may provide the basis of patient selection for surveillance programs and chemoprevention. This work is funded by RO1 CA102353to PPM.

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    PL05 - Genomics: From Research Tool to the Lung Cancer Clinic (ID 76)

    • Event: WCLC 2013
    • Type: Plenary Session
    • Track: Pathology
    • Presentations: 1
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      PL05.2 - Challenges in Bioinformatics (ID 797)

      16:45 - 17:10  |  Author(s): Y. Shyr

      • Abstract
      • Slides

      Abstract not provided

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