Author of

• 18972

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  P2.02 - Biology/Pathology (ID 616)

  • Event: WCLC 2017
  • Type: Poster Session with Presenters Present
  • Track: Biology/Pathology
  • Presentations: 1
  • Moderators:
  • Coordinates: 10/17/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)

  • 23263

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    P2.02-065 - RanBP9 is a Novel Prognostic and Predictive Biomarker for NSCLC and Affects Cellular Response to Cisplatin and PARP Inhibitors  (ID 10002)

    09:30 - 09:30  |  Author(s): M. Broggini
    • Abstract

    Background:
    We have previously demonstrated the involvement of Ran Binding Protein 9 (RanBP9) in the DNA Damage Response (DDR) in Non Small Cell Lung Cancer (NSCLC) cells. Here, we investigate its role in response to DNA-damaging agents in vitro and as prognostic and predictive biomarker for NSCLC patients.
    
    Method:
    First, by IHC, we evaluated RanBP9 expression in tumor vs normal adjacent tissue (NAT). Then, we generated A549 RanBP9 WT and KO NSCLC cells using CRISPR/Cas9. We treated A549 RanBP9 WT and KO with cisplatin (CDDP) and PARP inhibitors. We assessed response to treatment by measuring cell toxicity, apoptosis and proliferation. Finally, we determined the expression of RanBP9 in cohort of NSCLC patients previously enrolled in the TAILOR trial.
    
    Result:
    In the present study, we report that significant overexpression of RanBP9 is a common event in lung cancer, as shown by an extensive immunohistochemical analysis of RanBP9 levels in 148 lung tumors of different histotypes and their normal adjacent tissue (p<0.02 - 0.001). RanBP9 expression was maintained/acquired in the nodal metastasis from 30 NSCLC patients, indicating its potential involvement in tumor aggressiveness. We also show that RanBP9 KO A549 NSCLC cell lines display a reduced DDR and higher levels of apoptosis upon cisplatin treatment both in vitro and in vivo. Accordingly, a retrospective analysis of 134 NSCLC patients revealed that higher levels of RanBP9 are associated with tumor stage (p<0.0001), and low response to platinum compounds as first-line treatment (PFS, HR~ (RanBP9 positive versus negative)~ 1.71, 95% CI 1.142 - 2.563, p = 0.0093; OS HR~ (RanBP9 + vs -) ~1.942, 95% CI 1.243-3.033, p=0.0036). Finally, we show that ablation of RanBP9 is associated with overactivation of Poly(ADP-ribose) Polymerase (PARP) and increases sensitivity to PARP inhibitors. Moreover, that use of PARP inhibitors enhances cisplatin anti-neoplastic efficacy in the absence of RanBP9.
    
    Conclusion:
    We identified RanBP9 as a novel predictive biomarker of response to genotoxic treatments in NSCLC patients. We also report that RanBP9 affects the response of NSCLC cells to PARP inhibitors in vitro. Our results open new avenues for the treatment of NSCLC patients based on their level of expression of RanBP9.