Virtual Library
Start Your Search
Paula Llabata
Author of
-
+
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
-
+
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): Paula Llabata
- Abstract
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.
-
+
MA17 - Molecular Mechanisms and Therapies (ID 143)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Biology
- Presentations: 1
- Now Available
- Moderators:Eloisa Jantus-Lewintre, Hongbin Ji
- Coordinates: 9/09/2019, 15:45 - 17:15, Melbourne (1991)
-
+
MA17.05 - DNA-Binding and Gene Expression Profiles in Max Deficient Small Cell Lung Cancer (Now Available) (ID 377)
15:45 - 17:15 | Presenting Author(s): Paula Llabata
- Abstract
- Presentation
Background
The MYC pathway is frequently altered in cancer, mostly by gene activation of the MYC-family of oncogenes (fMYC) but also by genetic inactivation of MAX, the obligate partner of MYC. While the oncogenic properties of fMYC have been extensively studied, the tumour suppressor role of MAX and the function of fMYC in MAX-mutant cells remain unclear. Further, inactivating mutations in MGA, a gene that codes for another MAX-binding partner, have been found in lung cancer. MGA is a component of the non-canonical polycomb repressive complex 1 (ncPRC1) but its precise role in lung cancer development is unknown.
Method
RNA-sequencing, chromatin immunoprecipitation and proteomic analysis were performed to identify and compare the DNA binding and gene expression profiles of MYC, MGA and MAX in MAX-restituted human small cell lung cancer (SCLC)-derived cell lines.
Result
SCLC is a high-grade neuroendocrine type of lung cancer with recurrent inactivating mutations in MAX. Recent findings have described two major SCLC subtypes based on the high expression of either ASCL1 or NEUROD1 transcription factors. According to this, ASCL1 and NEUROD1 control the expression of different set of genes which defines the two subgroups of SCLC. Here, we found that MAX-mutant SCLC cells belong to the ASCL1-transcription factor dependent group of SCLCs. In the absence of MAX, even after ectopic overexpression of MYC, there was no recruitment of MYC to the DNA. The DNA binding profile of MAX in MAX-restituted cells remained unaltered after co-overexpression of MYC, despite opposed effects in gene expression. Moreover, restitution of MAX significantly shifted the DNA occupancy of MGA, from E2F6 consensus binding sites to MYC-consensus binding sites (E-boxes). Our observations also demonstrated that ncPRC1 complex is formed regardless of the presence or absence of MAX.
Conclusion
Our data supports that MYC lacks transactivation capabilities in the absence of MAX and that the tumour suppressor role of MAX relies on its capability to counteract the gene expression triggered by its partnering with fMYC. Further, we conclude that the tumor suppressor role of MGA may be related, in part, to the regulation of E2F6 promoters.
Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
