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  MA27 - Novel Drugs and PDX Models (ID 931)

  • Event: WCLC 2018
  • Type: Mini Oral Abstract Session
  • Track: Targeted Therapy
  • Presentations: 1
  • Moderators:
  • Coordinates: 9/26/2018, 13:30 - 15:00, Room 206 BD

  • 26220

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    MA27.11 - Genomic Sequencing and Editing Revealed the GRM8 Signaling Pathway as Potential Therapeutic Targets of Squamous Cell Lung Cancer (ID 12246)

    14:40 - 14:45  |  Author(s): Shaolei Li
    • Abstract
    • Slides

    Background
    

    Lung cancer is the leading cause of cancer death worldwide. Squamous cell carcinoma (LUSC) is one subtype of non-small-cell lung cancer (NSCLC), and ranks at the second of lung cancer incidence. Although targeting receptor tyrosine kinases (RTKs) had already brought better clinical outcomes to NSCLC patients carrying corresponding mutations, very few mutated targets had been identified in LUSC subtype, probably because of the lack of mutation hotspot and functional validation of mutated candidate.

    a9ded1e5ce5d75814730bb4caaf49419 Method
    

    The whole exome (WES) and whole genome (WGS) sequencing and CRISPR-Cas9 genome editing techniques were integrated to explore and validate novel targeting candidates from 11 groups of LUSC primary tumors and corresponding patient-derived xenografts (PDXs).

    4c3880bb027f159e801041b1021e88e8 Result
    

    The WES data revealed high homologies on the mutation types and signatures among primary tumor and different passages of PDX tumor samples. Nine significant genes carrying single nucleotide variations (SNVs) and three carrying copy number variations (CNVs) were identified as targeting candidates from WES and WGS data based on the mutation frequency and driver gene analysis. The oncogenic or tumor suppressor functions of those 12 candidates were validated through CRISPR-Cas9 loss-of-function system in tumor cells derived from PDX tissues carrying corresponding mutations and in normal bronchial epithelial cell-line. Furthermore, using CRISPRa transcriptionally activating system, one novel candidate, Metabotropic glutamate receptor 8 (GRM8) was elucidated to promote the survival of LUSC tumor cell through inhibiting cAMP pathway and activating MAPK pathway.

    8eea62084ca7e541d918e823422bd82e Conclusion
    

    The components of GRM8 signaling pathway could serve as potential targets of squamous cell lung cancer.

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