Abstract A112: RanBP9 protects cells from genotoxic stress and increased expression is predictive of worse response to platinum in NSCLC patients

Abstract

Abstract Platinum-based therapies currently represent the most common first-line treatment for non-small cell lung cancer (NSCLC). The efficacy of platinum compounds depends on the activation of the cellular DNA damage response (DDR), which leads to cancer cell death. However, severe toxic effects and development of resistance represent major limitations in the use of these drugs. Thus, a better mechanistic understanding and new prognostic and predictive biomarkers of the DDR are required to improve outcomes of NSCLC treatment. We have previously reported that RanBP9 (Palmieri et al., 2016), a poorly characterized scaffold protein, participates in the DDR and that its downregulation causes enhanced sensitivity to DNA damage induced by ionizing radiation. In the present study, we used immunohistochemical analysis to reveal that RanBP9 expression is significantly and commonly elevated in 178 lung tumors of different histotypes compared to their normal adjacent tissue (p<0.02 - 0.001). We also show that knockout (KO) of RanBP9 in A549 NSCLC cell lines resulted in reduced DDR and higher levels of cisplatin-induced apoptosis both in vitro and in vivo. These findings were validated by a retrospective analysis of 134 NSCLC patients in which higher levels of RanBP9 associated with tumor stage (p<0.0001), and poor response to platinum compounds as first-line treatment (PFS, HR (RanBP9 positive vs negative) 1.71, 95% CI 1.142 - 2.563, p = 0.0093). Finally, we show that ablation of RanBP9 is associated with overactivation of poly(ADP-ribose) polymerase (PARP) and increased cisplatin antineoplastic efficacy in combination with PARP inhibitors, indicating that the absence of RanBP9 results in a BRCAness-like phenotype. Overall, these results reveal that RanBP9 is a novel predictive biomarker of response to genotoxic treatments in NSCLC, paving the way to prospective studies aimed at assessing its clinical prognostic value and therapeutic targeting. Citation Format: Anna Tessari, Kareesma Parbhoo, Meghan Pawlikowski, Matteo Fassan, Eliana Rulli, Claudia Foray, Alessandra Fabbri, Valerio Embrione, Monica Ganzinelli, Marina Capece, Moray J. Campbell, Massimo Broggini, Krista La Perle, Gabriella Farina, Sara Cole, Mirko Marabese, Joseph M. Amann, David P. Carbone, Marina C. Garassino, Carlo M. Croce, Dario Palmieri, Vincenzo Coppola. RanBP9 protects cells from genotoxic stress and increased expression is predictive of worse response to platinum in NSCLC patients [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr A112.