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Walter Wang



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    P2.14 - Targeted Therapy (ID 183)

    • Event: WCLC 2019
    • Type: Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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      P2.14-19 - Notch3 and β-Catenin Are Frequently Co-Expressed in EGFR Mutant NSCLC (ID 2976)

      10:15 - 18:15  |  Author(s): Walter Wang

      • Abstract

      Background

      In the USA approximately 15% of the patients with lung adenocarcinoma have tumors associated with “driver” mutations in the EGFR gene that demonstrate major clinical responses to EGFR Tyrosine Kinase Inhibitors (EGFR TKIs). However, despite the fact that these mutations are always “truncal” (present in every tumor cell), and dramatic tumor shrinkage is seen initially in almost all patients, EGFR TKIs are never curative and tumors always recur. Some tumors that develop resistance appear to have pre-existing resistant sub clones, but the majority appear to acquire resistance by mutational target reactivation or bypass mechanisms. In order to develop acquired resistance, a subset of cells must survive at initial stage of therapy (“drug persister cells”, or DPCs) which are known to serve as a reservoir for accumulation mutation rendering drug resistance. We have demonstrated that Notch3 mediated β-catenin activation enables drug persistence, an essential step for the development of drug resistance.

      Method

      We have conducted tumor protein expression analysis on a tissue micro array (TMA) containing 86 NSCLC tumors obtained before therapy. These TMAs were subjected to IHC analysis to detect the expression of Notch3 and β-catenin signaling which is known to regulate drug persistence. We have also performed cell viability and biochemical assays under various perturbations to study drug persistence mechanisms in EGFR mutant NSCLC cells.

      Result

      Previously, we have demonstrated that EGFR TKI treatment leads to drug persistence through Notch3 mediated β-catenin activation. Using pre-treatment NSCLC patient tissue micro array (TMA) we identified that there is frequent co-expression of Notch3 and β-catenin (total) proteins in 90% of EGFR mutant NSCLC. We also observed that there are a relatively low proportion (10%) of patients with active β-catenin in these pretreatment samples. This suggests that the EGFR mutant tumors upregulate Notch3 protein expression, but that β-catenin is predominantly transcriptionally inactive before EGFR TKI treatment. We have also identified that Notch3 is a novel transcriptional target of β-catenin which in turn promotes both β-catenin and EGFR stability. These findings suggest that the Notch3 and inactive β-catenin co-expression is characteristic of EGFR mutant tumors, and β-catenin activation at baseline is infrequent. EGFR TKI therapy activates β-catenin signaling in a Notch3 dependent manner, and here we show that both proteins are frequently highly expressed in these tumors.

      Conclusion

      The concept of DPCs serving as a reservoir for accumulation of mutations that could cause drug resistance is novel. However, signaling pathways that are associated with the activation of drug persistence are not well characterized. For the first-time, our studies demonstrate that Notch3, β-catenin andEGFR regulate each other and EGFR TKI therapy mediated Notch3 activation leads to β-catenin activation which is essential for the maintenance of drug persister cells in a positive feedback loop. By understanding and targeting the Notch3 - β-catenin axis that control DPCs, these studies can develop therapeutics to prevent resistance to EGFR TKI therapy.