Oncotarget

Research Papers:

Treatment with the nitric oxide synthase inhibitor L-NAME provides a survival advantage in a mouse model of Kras mutation-positive, non-small cell lung cancer

Nicole L.K. Pershing _, Chi-Fu J. Yang, MengMeng Xu and Christopher M. Counter

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Oncotarget. 2016; 7:42385-42392. https://doi.org/10.18632/oncotarget.9874

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Abstract

Nicole L.K. Pershing1,*, Chi-Fu J. Yang2,*, MengMeng Xu1, Christopher M. Counter1,3

1Department of Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, NC, USA

2Department of Surgery, Duke University School of Medicine, Durham, NC, USA

3Department of Radiation Oncology, Duke University School of Medicine, Durham, NC, USA

*These authors have contributed equally to this work

Correspondence to:

Christopher M. Counter, email: count004@mc.duke.edu

Keywords: nitric oxide synthase, nitric oxide, non-small cell lung cancer, RAS, preclinical trial

Received: December 07, 2015    Accepted: May 12, 2016    Published: June 7, 2016

ABSTRACT

Oncogenic mutations in the gene KRAS are commonly detected in non-small cell lung cancer (NSCLC). This disease is inherently difficult to treat, and combinations involving platinum-based drugs remain the therapeutic mainstay. In terms of novel, pharmacologically actionable targets, nitric oxide synthases (NOS) have been implicated in the etiology of KRAS-driven cancers, including lung cancer, and small molecular weight NOS inhibitors have been developed for the treatment of other diseases. Thus, we evaluated the anti-neoplastic activity of the oral NOS inhibitor L-NAME in a randomized preclinical trial using a genetically engineered mouse model of Kras and p53 mutation-positive NSCLC. We report here that L-NAME decreased lung tumor growth in vivo, as assessed by sequential radiological imaging, and provided a survival advantage, perhaps the most difficult clinical parameter to improve upon. Moreover, L-NAME enhanced the therapeutic benefit afforded by carboplatin chemotherapy, provided it was administered as maintenance therapy after carboplatin. Collectively, these results support the clinical evaluation of L-NAME for the treatment of KRAS mutation-positive NSCLC.


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