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Y. He
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-099 - Differential Regulation of DNA Repair Genes in Cisplatin Resistant Non-Small Cell Lung Cancer Cells (ID 2746)
09:30 - 09:30 | Author(s): Y. He
- Abstract
Background:
In the absence of specific treatable mutations, cisplatin-based doublet chemotherapy remains the gold standard treatment for NSCLC patients. However, its clinical efficacy is hindered in many patients due to both intrinsic and acquired resistance to this drug. Alterations in the DNA repair capacity of damaged cells is now recognised as an important factor in mediating this phenomenon. DNA repair is therefore a vital target to improving cancer therapy and overcoming resistance of tumour cells to DNA damaging agents currently used in the treatment of NSCLC patients.
Methods:
DNA Repair Pathway RT[2 ]Profiler Arrays were used to elucidate the key DNA repair genes implicated in cisplatin resistant NSCLC cells using cisplatin resistant (CisR) and corresponding parental (PT) H460 NSCLC cells previously established in our laboratory. The regulation of the trans-activation of p53 in response to DNA damage was studied by examining protein accumulation, post-translational modifications (p53[Ser15]) and whether depletion of the novel DNA repair protein, hSSB1, affects the regulation of p53 in response to cisplatin. The repair of cisplatin-induced double strand breaks (DSBs) was examined by immunofluorescence imaging of γH2AX foci. Expression of p53[Ser15] (phosphorylated & total) in addition to hSSB1 was also assessed by HCA and Western blot analysis.
Results:
We identified a number of critical DNA repair genes that were differentially regulated between parental and cisplatin resistant NSCLC cells, some of which are known to be implicated in the nucleotide and mismatch repair pathways. H2AX was shown to be a reliable and specific marker of DNA double strand DNA breaks induced by platinum agents such as cisplatin. Cisplatin induced the translocation of p53 from the cytoplasmic compartment of H460 PT cells to the nuclear compartment, while significant levels of p53 were retained within the cytoplasmic compartment of CisR cells. Using both HCS and Western blot analysis, hSSB1 protein was undetectable.
Conclusion:
To date, despite reports that differential expression of components of the various DNA repair pathways correlate with response to cisplatin, translation of such findings in the clinical setting are warranted. The identification of alterations in specific proteins and pathways that contribute to these unique DNA repair pathways in cisplatin resistant cancer cells may potentially lead to a renewed interest in the development of rational novel therapies for cisplatin resistant cancers, in particular, lung cancer.
