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L. Croft

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    P1.02 - Biology/Pathology (ID 614)

    • Event: WCLC 2017
    • Type: Poster Session with Presenters Present
    • Track: Biology/Pathology
    • Presentations: 1
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      P1.02-071a - Targeting Human Single Stranded DNA Binding Protein (hSSB) 1, a Novel Prognostic Factor, in Non-Small Cell Lung Cancer (ID 9210)

      09:30 - 16:00  |  Author(s): L. Croft

      • Abstract
      • Slides

      Lung cancer is the leading cause of cancer death worldwide. The hallmark of all malignant disease is genomic instability leading to tissue invasion, metastasis and resistance to chemotherapy, notably cisplatin. hSSB1 is a guardian of the genome with a key role in the detection and repair of DNA double-strand breaks, replication fork arrest and oxidative stress damage. Recently we have shown that hSSB1 is directly phosphorylated by DNA-PK at serine residue 134 in response to replication stress to promote cellular survival. We hypothesized that hSSB1 may play a role in the pathogenesis of non-small cell lung cancer (NSCLC) and in the mechanism of resistance to cisplatin based chemotherapy observed for (NSCLC). Therefore we evaluated the role of hSSB1 as a prognostic factor and as a potential new target for therapy.

      We analyzed the prognostic significance of hSSB1 mRNA expression from public on line databases and through assessment of protein expression in an NSCLC tissue macro-array (TMA) using immunohistochemistry. hSSB1 mRNA levels were analyzed in matched normal:tumour adenocarcinoma and squamous cell tumour samples, and in a platinum sensitive vs resistant cells. We also explored the impact of hSSB1 expression on NSCLC cell lines sensitivity to cisplatin (measured by cell proliferation) by over-expressing a Flag tagged hSSB1 or depleting hSSB1 with specific small interfering (si)RNA.

      hSSB1 expression was associated with poor prognosis for lung cancer, high levels of mRNA and protein expression correlating with a worse overall survival. hSSB1 mRNA levels were prognostic in adenocarcinomas only. hSSB1 mRNA was also significantly increased in both adenocarcinoma and squamous cell carcinoma compared to matched normal tissue. Furthermore, we observed that hSSB1 was upregulated in H460 cisplatin resistant cells as compared to the parental line. Knockdown of hSSB1 in H460 cells was associated with a significant increase in sensitivity to cisplatin.

      Our results establish hSSB1 as a prognostic factor in non-small cell lung cancer. Moreover, targeting hSSB1 may prove an effective method of reversing platinum resistance. Evaluation of the potential role of DNA-PK inhibition in inhibiting hSSB1 activation and reversing cisplatin and radiotherapy resistance in tumours with high levels of hSSB1 expression is currently ongoing.

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