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W.W. Lockwood



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    OA 07 - Biomarker for Lung Cancer (ID 659)

    • Event: WCLC 2017
    • Type: Oral
    • Track: Biology/Pathology
    • Presentations: 1
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      OA 07.07 - Inhibition of the Novel Oncogene ELF3 Abolishes Lung Adenocarcinoma Growth (ID 8408)

      15:45 - 17:30  |  Author(s): W.W. Lockwood

      • Abstract
      • Presentation
      • Slides

      Background:
      Oncogenic reactivation of transcription factors involved in fetal lung development is integral to lung adenocarcinoma (LUAD) biology, as observed with TITF1/NKX2-1 and the ETS transcription factors ETV4 and ETV5. ELF3 is an uncharacterized ETS family member implicated in fetal lung development encoded at 1q32.1. Interestingly, chromosome 1q is a region of frequent gain in LUAD that lacks a bona fide oncogene. We hypothesize that ELF3 is a novel oncogene and putative therapeutic target in LUAD.

      Method:
      Multiple independent datasets encompassing 1,685 clinical samples of LUAD, lung squamous cell carcinoma (LUSC), small cell lung cancer, and non-malignant lung tissues were analyzed to establish the frequency of ELF3 overexpression and underlying genetic mechanisms of selection. Protein-protein interaction (PPI) networks were constructed around ELF3, and integrated pathway analysis was performed to decipher the signaling network disruptions resulting from ELF3 overexpression. Isogenic cell lines were established to assess the ability of ELF3 to regulate oncogenic phenotypes. The effect of ELF3 loss on tumour growth was assessed in xenograft mouse models.

      Result:
      Strong ELF3 overexpression was frequently observed in LUAD (>2-fold: TCGA 40% p=1.5E-07; BCCA 73% p=1.6E-21), but was not observed in other lung cancer subtypes. Similarly, high ELF3 expression was significantly associated with poor overall survival of LUAD patients (all Stages p<0.0001, Stage I p<0.0001), but not LUSC patients (p>0.05). These clinical associations prompted further examination of ELF3 in the LUAD subtype of lung cancer. While mutations in ELF3 were rare, up to 80% of LUAD patients harboured focal amplification, DNA gain, and/or promoter hypomethylation at the ELF3 locus, which resulted in transcript overexpression. ELF3 overexpression induces remodeling of 23 direct PPI networks, resulting in loss of interaction with proteins such as MYC and GLI2, while forming new interactions with NKX2-1, HOXA5 and CDK8, among others. This reprogramming of PPI networks affects multiple oncogenic pathways including MAPK, TGF-beta and WNT. ELF3 knockdown in LUAD cell lines resulted in significantly reduced proliferation, viability, and anchorage-independent growth, demonstrating ELF3 has oncogenic properties. Loss of ELF3 abolished the ability of LUAD cells to establish tumours in xenograft mouse models, demonstrating the requirement of ELF3 expression for tumour growth.

      Conclusion:
      ELF3 is a novel LUAD oncogene encoded on chromosome 1q, activated in up to 73% of patients, and strongly associated with poor overall survival. As ELF3 inhibition abolished tumour growth, therapeutic targeting of ELF3 could benefit LUAD patient outcome.

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