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Francisco Exposito
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P1.09 - Pathology (ID 173)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Pathology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.09-13 - Prognostic Value of TMPRSS4 Expression and Its Role as Diagnostic Biomarker by Liquid Biopsy in Early Stage NSCLC (ID 2499)
09:45 - 18:00 | Presenting Author(s): Francisco Exposito
- Abstract
Background
Relapse rates in surgically-resected non-small cell lung cancer (NSCLC) patients are between 30-45% within 5 years of diagnosis, which reflects the clinical need to identify those patients at high risk of recurrence and death. TMPRSS4 is a serine protease that plays a role in lung cancer growth, development of metastasis and resistance to chemotherapy in NSCLC models. TMPRSS4 is overexpressed through promoter hypomethylation in NSCLC tumors.
Method
Two cohorts of NSCLC patients (MD Anderson (MDA), n=489; and Clinica Universidad de Navarra (CUN), n=95) were used to investigate the prognostic value of TMPRSS4. The WHO 2004 classification and 8th TNM edition was used for tumor stratification. We have also developed a method to quantify he degree of TMPRSS4 and SHOX2 methylation status in liquid biopsy (plasma and bronchoalveolar lavages (BALS)) by digital droplet PCR (ddPCR), in tumor-free individuals and patients with NSCLC.
Result
High levels of TMPRSS4 were significantly associated with reduced relapse-free survival (RFS, p<0.001) and overall survival (OS, p<0.001) in the MDA cohort, and with OS in the CUN cohort (p<0.049). In univariate Cox regression analysis using the MDA cohort, high TMPRSS4 levels were RFS (HR=2.09; 95% IC [1.53-2.87], p<0.001) and OS (HR=1.82; 95% IC [1.38-2.41], p<0.001). In multivariate analyses, TMPRSS4 was found as an independent prognostic factor for both RFS (HR=1.82, IC [1.28-2.60], p<0.001) and OS (HR=1.44, IC [1.07-1.94], p<0.014).
Conclusion
In our MDA cohort, stage IA and stage IB showed no statistical differences for RFS (p=0.27) or OS (p<0.001). However, when considering the protein expression of TMPRSS4 we were able to substratify stage IA patients in low and high risk patients, since those with high TMPRSS4 levels showed a significantly reduced RFS (p=0.002) and OS (p<0.001). Similar tendency was observed for stage IB, although statistical differences were not found.
After successful establishment of the ddPCR conditions for TMPRSS4 and SHOX2 methylation status, we analyzed plasmas and BALS in case-control studies. In BALS (79 NSCLC patients and 26 controls), significant hypomethylation (p<0.01) was found for TMPRSS4 in the case of patients with early stage NSCLC in comparison with controls, with an AUROC of 0.72 (95% IC, 0.57-0.87) (p=0.008). SHOX2 was significantly hypermethylated in BALS from early stage NSCLC compared to controls (p<0.01), with an AUROC of 0.71 (95% IC, 0.56- 0.86) (p=0.01). In the case of plasmas (89 NSCLC patients and 25 controls): in early stages, a significant hypomethylation was found for TMPRSS4 (p<0.05), with an AUROC of 0.73 (95% IC, 0.54-0.90) (p=0.015). For SHOX2, only late stages NSCLC showed significant hypermethylation with respect to controls (p<0.05), with an AUROC of 0.68 (95% IC, 0.54-0.80) (p=0.025).
High TMPRSS4 levels are associated with worse prognosis in NSCLC patients. TMPRSS4 expression significantly discriminates patients with higher risk of disease progression and poor survival outcome in early stage NSCLC. Methylation status of TMPRSS4 can be used in both plasma and BALS to identify patients with NSCLC.
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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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P2.03-38 - Identification of a Novel Synthetic Lethal Vulnerability in Non-Small Cell Lung Cancer by Co-Targeting TMPRSS4 and DDR1 (ID 2191)
10:15 - 18:15 | Author(s): Francisco Exposito
- Abstract
Background
Synthetic lethality has been defined as the inability of cells to proliferate when co-targeting two genes, with a synergistically superior inhibition than that found for each individual gene. Consistent co-expression of two genes involved in a similar function is a predictor of synthetic lethality, a strategy that is being applied to find out novel cancer vulnerabilities.
Method
Large-scale bioinformatics analyses across 5 public databases were used to identify genes consistently co-expressed with TMPRSS4, a novel therapeutic target that we have previously identified in NSCLC. Pyrosequencing was used to evaluate methylation levels in patients and cell lines. Functional in vitro experiments and animal models were used to assess synthetic lethality of TMPRSS4 and DDR1 in NSCLC.
Result
Consistent co-expression between TMPRSS4 and DDR1 was found in all NSCLC databases evaluated. Similar to TMPRSS4, DDR1 promoter was hypomethylated in NSCLC in 3 independent cohorts and hypomethylation was an independent prognostic factor of disease-free survival. Treatment with 5-azacitidine increased DDR1 levels in cell lines, suggesting an epigenetic regulation. Cells lacking TMPRSS4 were highly sensitive to the cytotoxic effect of the DDR1 inhibitor dasatinib. TMPRSS4/DDR1 double knock-down cells, but not single knock-out cells suffered a G0/G1 cell cycle arrest with loss of E2F1 and cyclins A and B, increased p21 levels and apoptosis. Moreover, double knock-down cells were highly sensitized to cisplatin, which caused massive apoptosis (~40%). In vivo studies demonstrated tumor regression in mice injected with double knock-down-injected cells and lack of 18FDG-uptake by microPET analysis.
Conclusion
We have identified a novel vulnerability in NSCLC resulting from a synthetic lethal interaction between DDR1 and TMPRSS4. This may help designing therapeutic strategies to impair NSCLC growth by co-targeting both genes.
