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Andrea Vilarrubí Porta



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    EP1.14 - Targeted Therapy (ID 204)

    • Event: WCLC 2019
    • Type: E-Poster Viewing in the Exhibit Hall
    • Track: Targeted Therapy
    • Presentations: 1
    • Now Available
    • Moderators:
    • Coordinates: 9/08/2019, 08:00 - 18:00, Exhibit Hall
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      EP1.14-39 - BRG1 Deficient Cells Are Sensitive to the Inhibition of Specific Lysine Demethylases (KDMs) in Lung Cancer  (Now Available) (ID 634)

      08:00 - 18:00  |  Author(s): Andrea Vilarrubí Porta

      • Abstract
      • Slides

      Background

      The standard treatment of non-small cell lung cancer (NSCLCs) is surgery. New therapeutics, such as tyrosine kinase inhibitors or immunotherapy may improve survival, but these treatments are only effective in small cohorts of patients. Thus, hopes of improving survival of lung cancer patients are related to the advent of novel therapeutic strategies. The classic epigenetic research focuses in the reversion of gene promoter DNA hyper methylation or histone code modifications, using a battery of unspecific drugs addressed to modify the global epigenetic code in cancer cells. In our previous work, we identified frequent inactivating mutations in the epigenetic gene BRG1 (about 20% of NSCLC), which were mutually exclusive with amplifications in the MYC oncogenic family. Unfortunately, BRG1-mutant cancer cells were also not able to respond to certain epigenetic therapies whereas cancer cells carrying MYC amplification, which are BRG1 proficient, appear to be highly sensitive to these combinations of treatments. These results show that MYC amplification could be used as a prognostic biomarker for a specific personalized therapy. In this project we observed that the mutational status of BRG1 directly correlates with the expression levels of several Lysine methyltransferases (KMTs) and Lysine demethylases (KDMs) in cancer cells. We also found that inactivating mutations in KDMs and KMTs tend to be mutually exclusive with inactivating mutations in BRG1, mutations in other SWI/SNF members and mutations in MYC oncogenic genes. Thus, we focused on targeting histone-modifying enzymes, in BRG1 proficient or deficient lung cancers cell lines.

      Method

      For this propose we integrate state of the art technology like genome-wide chromatin modification and transcriptome analysis, using human cell lines and preclinical models for lung cancer, including in vivo models of mice such as xenografts, subjected at different concentrations of histone deacetylase inhibitor (HDACi), lysine demethylase inhibitor (KDMi) and EZH2 inhibitor (EZH2i) to design a personalized epigenetic treatment with high efficacy and low toxicity.

      Result

      Our results showed that BRG1 deficient cells are not sensitive to HDACi, displaying an unexpected increase in some epigenetic marks after treatment that correlates with a global enrichment of repressive marks and EZH2 occupancy at gene promoter in BRG1-mutant cells. Otherwise, BRG1 directly regulates KDMs expression in lung cancer and demonstrates that inactivating mutations in BRG1 sensitizes cancer cells to the lysine demethylase inhibitor (KDMi). However, EZH2i seems to reverse KDMi activity in the absence of BRG1, exposing an interesting and determining role of this histone lysine methyltransferase in the sensitization of BRG1 deficient cancer cells to the KDMi.

      Conclusion

      The results will be of great value for the stratification of lung tumors according to their genetic or epigenetic background for tailored treatments, opening the possibility to use BRG1 mutations as a potential Biomarker for personalized epigenetic target therapy in cancer. The development of an epigenetic-based therapeutic prediction model will hopefully set the basis for future treatment of lung cancer as well as of other epithelial cancers.

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