Author of

• 15517

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  P3.05 - Poster Session/ Prevention and Tobacco Control (ID 217)

  • Event: WCLC 2015
  • Type: Poster
  • Track: Prevention and Tobacco Control
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/09/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)

  • 15519

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    P3.05-002 - Heterogeneity of Metformin Response for Lung Cancer Chemoprevention (ID 2942)

    09:30 - 09:30  |  Author(s): M. Barron
    • Abstract

    Background:
    Squamous cell carcinoma accounts for about 25-30% of all non-small cell lung cancers. Metformin is a drug commonly prescribed as first-line treatment for type-2 diabetes, with some evidence showing that the drug can also act directly on cancer cells. Recent observational studies and meta-analysis show that diabetic patients who are long term users of metformin have lower risk for breast cancer and that metformin use lowered cancer development in the liver and lung. The goal of this study was to determine metformin response in different cell lines and different cellular contexts, and to use that information to work towards the generation of a metformin “sensitivity index” that could be used guide individualized chemoprevention.
    
    Methods:
    We performed cell survival analysis to assess differences in the sensitivity of patient-derived fibroblast cells and squamous cancer cell lines exposed to metformin. We also evaluated metformin response of Nkx2.1 positive lung progenitor cells that were differentiated from induced pluripotent stem (iPS) cells to identify differences for cells in different cellular contexts. Gene expression profiling and DNA sequencing analyses were performed to identify genes, pathways and genomic alterations that mediate metformin response in order to generate a “sensitivity index” for predicting metformin response.
    
    Results:
    Cell survival analysis showed that different cell lines respond differently to metformin, and cells of identical genotypes in a variety of differentiated states or cellular contexts also show differential response to metformin. Gene expression profiling of metformin treated cells identified eight differentially expressed gene including ADH1B, TMEM161B, CPED1, SNAI2, FOXF1 and DLGAP1 that may mediate metformin response. Exome sequencing and analysis identified unique single nucleotide variants (SNV) in TRAF3IP3, DMBT1, RIT2, SERPINB2, PIK3R2 that were present in all non-responders but absent in all responders. SNVs and indels present in all responders but absent in all non-responders included those in GRK7, SMARCA5, CTSB, CHD4, PLCB2, ZADH2, RPLP2, CLASP2, NEDD4, DNAH17, CPXCR1, LDHD and CLTC.
    
    Conclusion:
    Differences in response to metformin treatment across a variety of cell lines and cellular contexts suggest heterogeneity that may be patient-specific. A list of differentially expressed genes and genetic mutations can be used as a metformin “sensitivity index” to stratify patients into metformin responders and non-responders and guide individualized chemoprevention.