Author of

• 35874

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  P69 - Tumor Biology and Systems Biology - Basic and Translational Science - RTK/EGFR (ID 208)

  • Event: WCLC 2020
  • Type: Posters
  • Track: Tumor Biology and Systems Biology - Basic and Translational Science
  • Presentations: 1
  • Moderators:
  • Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall

  • 35883

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    P69.05 - Molecular and Cellular Heterogeneity Underpin Treatment Response Across a Spectrum of EGFR-Mutant Non-Small Cell Lung Cancer (ID 1681)

    00:00 - 00:00  |  Presenting Author(s): Ju Yuan
    • Abstract

    Introduction
    

    Non-small cell lung cancer (NSCLC) present a large proportion of intratumoral heterogeneity. The genetic heterogeneity affects key cancer pathways, driving phenotypic variation, and heterogeneous present in environmental parameters that influence cell metabolism, which poses a significant challenge to efficacy of targeted therapies and gaining clinical resistance.

    Methods
    

    Many monoclonal cell lines were derived from each of four EGFR-mutant non-small cell lung cancer (NSCLC) tumors, including treatment-naive/experienced, as well as primary/metastatic tumors. These cell lines were subjected to high-throughput genotyping (whole genome/exome sequencing) and phenotyping (RNA-seq, drug screens), with validation in PDX mouse models.

    Results
    

    We were able to recapitulate patient resistance to the different generations of tyrosine-kinase inhibitors (TKIs) in corresponding patient-derived cell lines. Cell lines derived from single primary tumors were more heterogeneous in their accumulated mutations and their response to a 317-compound anti-cancer drug library, compared to cell lines derived from single metastatic tumors. Overall, we find that clonal genetic and phenotypic heterogeneity tracked with response to the drug library. We were able to identify drug resistant clones by their gene expression profiles, and suggest alternative drugs to specifically target such populations in a tumor.

    Conclusion
    

    We establish a framework for the genotypic and phenotypic dissection of clonal populations within a tumor and find that clonal genetic and phenotypic diversity are propagated as heterogeneity in response to drugs. This approach will be applicable for identifying persistent drug resistant subpopulations within a tumor through their expression profiles, and to suggest alternative approaches for therapeutically targeting such cells.