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Eva Pros
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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): Eva Pros
- 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.
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P1.03 - Biology (ID 161)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.03-26 - Genetic and Molecular Profiling of Non-Smoking Related Lung Adenocarcinomas (ID 1701)
09:45 - 18:00 | Presenting Author(s): Eva Pros
- Abstract
Background
The etiology and many details of the genomic profile and molecular basis of lung adenocarcinomas (LuADs) in nonsmoker patients remain elusive. Further, the scarcity of primary cultures available from non-smoking related lung adenocarcinomas (NSK-LuADs) contributes to hamper our biological understanding of these tumors.
Method
We established patient-derived cancer cell (PDCs) cultures from NSK-LuADs, and performed whole exome sequencing (WES) and RNA sequencing (RNA-seq) analysis to delineate their genomic architecture. For validations, we analyzed independent cohorts of LuADs.
Result
The analysis revealed non-smoker related alterations such as those at the growth factor receptors RET, ALK, EGFR and ERBB2. There were also mutations affecting signal transduction molecules such as AKT1, BRAF and KRAS, and mutations in tumor suppressor genes, including TP53, CDKN2A, RB1, ARID1A, ATM and STK11. We also identified new fusions and recurrent mutations in some genes, one of them, a possible regulator of gene expression, affecting ten percent of the LuADs, thus constituting a potentially relevant tumor suppressor gene. We also report a predominance of RB1-inactivation, mostly complex intragenic rearrangements (homozygous deletions or duplications) in EGFR-mutant tumors. Three EGFR-/RB1-mutant tumors, treated with EGFR-TKIs, and one EGFR-wild type tumor, treated with standard chemotherapy, developed small cell lung cancer and/or squamous cell carcinoma transformation, evident in the re-biopsies and/or PDCs. Finally, we found pathogenic germ-line mutations at genes associated to familiar-cancer syndromes, especially the TP53-associated Li Fraumeni syndrome, affecting ten percent of EGFR-mutant LuADs patients, underscoring a genetic predisposition origin for a subset of NSK-LuADs.
Conclusion
The recurrent gene inactivation found in candidate gene in LuADs heralds a tumor suppressor role which deserves further exploration. The pre-existent inactivation of RB1 predominates in EGFR-mutant tumors and may underlie an extremely ductile nature, albeit additional gene alterations are required to overcome sensitivity to the TKIs. Given their potential clinical and therapeutic implications, testing for RB1-alterations and for the Li-Fraumeni syndrome in EGFR-mutant LuADs patients may need to be incorporated in the clinical settings.
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P2.03 - Biology (ID 162)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Biology
- Presentations: 1
- Moderators:
- Coordinates: 9/09/2019, 10:15 - 18:15, Exhibit Hall
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P2.03-03 - Landscape of Gene Fusions in Lung Adenocarcinoma Patients with Minimal Cigarette Exposure Identified on Malignant Pleural Effusions (ID 575)
10:15 - 18:15 | Author(s): Eva Pros
- Abstract
Background
Gene fusions in lung adenocarcinoma (LuAD) involving tyrosine kinase receptors such as ROS1, ALK or RET are recurrent oncogenic drivers (~10%), enriched in light or never-smokers. Some of them represent emerging and predictive biomarkers for targeted therapies. Here we report the fusions detected in a cohort of metastatic LuAD patients with low tobacco exposure (never or former-smokers).
Method
Patient-derived cancer cell lines (PDC) were successfully established from malignant pleural effusions from 11 patients diagnosed with LuAD. We assessed the genetic and molecular profile by whole-exome sequencing (WES) and RNA sequencing (RNA-seq) in each cell line.
Result
Patients’ characteristics: median age, 58 (39-86); 9 were female. Eight of eleven were never-smokers and three, former-smokers. Seven patients were treatment naïve when pleural effusion samples were collected. A cytological examination of pleural fluid was performed by a lung pathologist and all samples were positive for malignant cells. Known driver mutations in lung primary tumours included one ALK translocation detected by FISH and three EGFR Del19 mutations by targeted sequencing. The three EGFR-mutant LuAD patients progressed to first or second-generation EGFR-TKI and we were able to stablish paired PDC after progressing to tyrosine kinase inhibitors (TKI) in two of them. We identified an acquired FGFR3-TACC3 fusion in one paired PDC after gefitinib progression (T790M-negative), that led to overexpression of FGFR3 concurrent with an enrichment of squamous cell lineage transcripts (e.g. TP63, SOX2) and MDM2 amplification. Among EGFR wild type (wt) patients, two RET rearrangements, CCDC6-RET and KIF5B-RET, and one EML4-ALK fusion -also detected in the primary tumour- were identified in PDC models. In addition, in two of the samples we discovered novel gene fusions that will be described in detail, involving proteins that are not kinases, and thus, their potential role in cancer is still unknown.
Conclusion
In this cohort enriched with never-smoking LuAD patients presenting pleural effusions at diagnosis, the presence of known driver fusions during the disease’s course detected by RNA-Seq was 36% (4/11), including a FGFR3-TACC3 fusion as an acquired resistance mechanism to EGFR-TKI. Further study is ongoing in our PDC models to test the functional role of these fusions in order to facilitate precision medicine.
