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S. Fox

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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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      P1.02-071b - SASH1 Is a Prognostic Indicator and Future Target in NSCLC (ID 9591)

      09:30 - 16:00  |  Author(s): S. Fox

      • Abstract
      • Slides

      Lung cancer is the most commonly diagnosed cancer in the world and the fifth most common in Australia, where it is responsible for almost one in five cancer deaths. SASH1 (SAM and SH3 domain-containing protein 1) is a tumor suppressor functioning to control of apoptosis and cellular proliferation. Previously SASH1 has been shown to be down-regulated in approximately 90% of lung cancers, however little is known about the role of SASH1 in the pathogenesis of the disease. Cytotoxic platinum based chemotherapy two-drug regimens remain a cornerstone NSCLC patient care, however, resistance to these agents is almost inevitable. The re-sensitisation of these cancer cells to chemotherapeutics is a key to improving patient survival. We hypothesised that modulation of SASH1 expression may alter cisplatin sensitivity.

      A panel of lung cancer cell lines depleted of SASH1 (siRNA) or overexpressing SASH1 were analysed for protein levels via immunoblotting, cell proliferation, and survival/death assays. Treatment of lung cancer cells with the SASH1 protein stabilising compound chloropyramine (0-50 μM) and/or cisplatin (0-10 μM) was performed followed by immunoblotting for SASH1, cell proliferation, and survival/death assays. SASH1 IHC staining of adenocarcinoma and Squamous cell carcinomas was correlated with patient survival.

      We demonstrated that SASH1 depletion results in a significant increase in cellular proliferation of NSCLC cancer cells. The depletion of SASH1 within lung cancer cell lines was associated with a significant increase in cisplatin resistance. Transfection of SASH1 into NSCLC cell lines induced cell death. The treatment of cells with the SASH1 protein stabilising compound chloropyramine increased SASH1 levels, reduced proliferation and induced apoptosis. Furthermore, chloropyramine increased cisplatin sensitivity. The relationship between SASH1 protein expression with overall survival was accessed in a NSCLC TMA panel. This showed that high SASH1 protein levels were associated with a poor prognosis in adenocarcinomas but were non-prognostic in squamous cell disease. Interestingly high SASH1 mRNA levels were associated with a favourable prognosis in adenocarcinoma but were not prognostic in squamous cell cancer. In a panel of cancer cell lines we observed no correlation between mRNA and protein levels that may explain this discrepancy.

      Agents that upregulate SASH1, or SASH1 gene therapy, are potential novel approaches to the management of NSCLC. Further preclinical and clinical studies of chloropyramine in combination with chemotherapy are justified in NSCLC.

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