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Published on: September 30, 2016
RANBP9 as potential therapeutic target in non-small cell lung cancer
Anna Tessari1, Shimaa H A Soliman1,2,3, Arturo Orlacchio1
1Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University and Arthur G. James Comprehensive Cancer Center, Columbus, OH 43210, USA.
Abstract:
Non-small cell lung cancer (NSCLC) remains the leading cause of cancer-related deaths in the Western world. Despite progress made with targeted therapies and immune checkpoint inhibitors, the vast majority of patients have to undergo chemotherapy with platinum-based drugs. To increase efficacy and reduce potential side effects, a more comprehensive understanding of the mechanisms of the DNA damage response (DDR) is required. We have shown that overexpressby live cell imaging (Incuyion of the scaffold protein RAN binding protein 9 (RANBP9) is pervasive in NSCLC. More importantly, patients with higher levels of RANBP9 exhibit a worse outcome from treatment with platinum-based drugs. Mechanistically, RANBP9 exists as a target and an enabler of the ataxia telangiectasia mutated (ATM) kinase signaling. Indeed, the depletion of RANBP9 in NSCLC cells abates ATM activation and its downstream targets such as pby live cell imaging (Incuy53 signaling. RANBP9 knockout cells are more sensitive than controls to the inhibition of the ataxia and telangiectasia-related (ATR) kinase but not to ATM inhibition. The absence of RANBP9 renders cells more sensitive to drugs inhibiting the Poly(ADP-ribose)-Polymerase (PARP) resulting in a "BRCAness-like" phenotype. In summary, as a result of increased sensitivity to DNA damaging drugs conferred by its ablation in vitro and in vivo, RANBP9 may be considered as a potential target for the treatment of NSCLC. This article aims to report the results from past and ongoing investigations focused on the role of RANBP9 in the response to DNA damage, particularly in the context of NSCLC. This review concludes with future directions and speculative remarks which will need to be addressed in the coming years.
Insights
Overexpressing scaffold protein RAN binding protein 9 (RANBP9) worsens outcomes in non-small cell lung cancer (NSCLC) patients treated with platinum drugs. Depleting RANBP9 increases sensitivity to DNA damaging agents, suggesting it as a therapeutic target.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Non-small cell lung cancer (NSCLC) is a leading cause of cancer mortality, with platinum-based chemotherapy remaining a primary treatment modality.
- Understanding DNA damage response (DDR) mechanisms is crucial for improving chemotherapy efficacy and reducing side effects in NSCLC.
- Overexpression of the scaffold protein RAN binding protein 9 (RANBP9) is frequently observed in NSCLC and correlates with poor treatment outcomes.
Purpose of the Study:
- To investigate the role of RANBP9 in the DNA damage response within NSCLC.
- To explore the potential of targeting RANBP9 for enhancing the efficacy of DNA damaging agents in NSCLC treatment.
Main Methods:
- Utilized live cell imaging to assess RANBP9 expression.
- Conducted experiments involving RANBP9 depletion and knockout in NSCLC cells.
- Assessed cellular sensitivity to DNA damaging agents, including ATM and ATR kinase inhibitors, and PARP inhibitors.
- Examined the impact of RANBP9 on ATM signaling pathways.
Main Results:
- RANBP9 overexpression is prevalent in NSCLC and associated with worse outcomes from platinum-based chemotherapy.
- Depletion of RANBP9 inhibits ATM activation and downstream signaling, increasing sensitivity to ATR kinase inhibitors.
- RANBP9-deficient cells exhibit increased sensitivity to Poly(ADP-ribose)-Polymerase (PARP) inhibitors, displaying a "BRCAness-like" phenotype.
- Ablation of RANBP9 enhances sensitivity to DNA damaging drugs both in vitro and in vivo.
Conclusions:
- RANBP9 plays a significant role in the DNA damage response in NSCLC.
- Targeting RANBP9 could represent a novel therapeutic strategy to improve responses to DNA damaging agents in NSCLC patients.
- Further research is warranted to explore the clinical implications of targeting RANBP9.
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