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RANBP9 affects cancer cells response to genotoxic stress and its overexpression is associated with worse response to platinum in NSCLC patients

Oncogene volume 37, pages 6463–6476 (2018)Cite this article

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Abstract

Although limited by severe side effects and development of resistance, platinum-based therapies still represent the most common first-line treatment for non-small cell lung cancer (NSCLC). However, a crucial need in the clinical management of NSCLC is represented by the identification of cases sensitive to DNA damage response (DDR)-targeting drugs, such as cisplatin or PARP inhibitors. Here, we provide a molecular rationale for the stratification of NSCLC patients potentially benefitting from platinum compounds based on the expression levels of RANBP9, a recently identified player of the cellular DDR. RANBP9 was found overexpressed by immunohistochemistry (IHC) in NSCLC compared to normal adjacent tissues (NATs) (n = 147). Moreover, a retrospective analysis of 132 platinum-treated patients from the multi-centric TAILOR trial showed that RANBP9 overexpression levels are associated with clinical response to platinum compounds [Progression Free Survival Hazard Ratio (RANBP9 high vs low) 1.73, 95% CI 1.15–2.59, p = 0.0084; Overall Survival HR (RANBP9 high vs low) 1.99, 95% CI 1.27–3.11, p = 0.003]. Accordingly, RANBP9 KO cells showed higher sensitivity to cisplatin in comparison with WT controls both in vitro and in vivo models. NSCLC RANBP9 KO cells were also more sensitive than control cells to the PARP inhibitor olaparib alone and in combination with cisplatin, due to defective ATM-dependent and hyper-activated PARP-dependent DDR. The current investigation paves the way to prospective studies to assess the clinical value of RANBP9 protein levels as prognostic and predictive biomarker of response to DDR-targeting drugs, leading to the development of new tools for the management of NSCLC patients.

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Acknowledgements

Authors are thankful to Dr. R. Shakya and the Target Validation Shared Resource, the Campus Microscopy & Imaging Facility, the Analytical Cytometry Shared Resource, the Comparative Pathology and Mouse Phenotyping Shared Resource, the Genetically Engineered Mouse Modeling Core, and N. Single and L. Monovich of the Biospecimen Services Shared Resource of the Ohio State University-Comprehensive Cancer Center. A.T. and M.P. are recipients of a Pelotonia Fellowship for Cancer Research. This work was supported by start-up funds to V.C. from the College of Medicine, Office of Research, and Comprehensive Cancer Center of the Ohio State University.

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Affiliations

  1. Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University and Arthur G. James Comprehensive Cancer Center, Columbus, OH, 43210, USA

    Anna Tessari, Kareesma Parbhoo, Meghan Pawlikowski, Claudia Foray, Valerio Embrione, Marina Capece, Marianna Hernandez, Carlo M. Croce, Dario Palmieri & Vincenzo Coppola

  2. Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, Italy

    Matteo Fassan

  3. Department of Oncology, IRCCS - Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy

    Eliana Rulli, Massimo Broggini & Mirko Marabese

  4. Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    Alessandra Fabbri

  5. Thoracic Oncology Unit, Department of Medical Oncology, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy

    Monica Ganzinelli & Marina C. Garassino

  6. Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, 536 Parks Hall, Columbus, OH, 43210, USA

    Moray J. Campbell

  7. Department of Veterinary Biosciences and Comparative Pathology and Mouse Phenotyping Shared Resource, College of Veterinary Medicine, The Ohio State University and Arthur G. James Comprehensive Cancer Center, Columbus, OH, USA

    Krista La Perle

  8. Department of Oncology, Ospedale Fatebenefratelli and Oftalmico, Milan, Italy

    Gabriella Farina

  9. Campus Microscopy and Imaging Facility, The Ohio State University, Columbus, OH, 43210, USA

    Sara Cole

  10. Department of Internal Medicine, College of Medicine, James Thoracic Center, Ohio State University and Arthur G. James Comprehensive Cancer Center, Columbus, OH, 43210, USA

    Joseph M. Amann & David P. Carbone

  11. Division of Pathology, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy

    Giancarlo Pruneri

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Tessari, A., Parbhoo, K., Pawlikowski, M. et al. RANBP9 affects cancer cells response to genotoxic stress and its overexpression is associated with worse response to platinum in NSCLC patients. Oncogene 37, 6463–6476 (2018). https://doi.org/10.1038/s41388-018-0424-8

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