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.
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.
Department of Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, NC, USA.
Nicole L K
NL
Pershing
Department of Surgery, Duke University School of Medicine, Durham, NC, USA.
Chi-Fu Jeffrey
CFJ
Yang
Department of Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, NC, USA.
MengMeng
M
Xu
Department of Pharmacology & Cancer Biology, Duke University School of Medicine, Durham, NC, USA.|Department of Radiation Oncology, Duke University School of Medicine, Durham, NC, USA.
Christopher M
CM
Counter
D000483:Alleles; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D016190:Carboplatin / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D011905:Genes, ras; D006579:Heterozygote; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics; D008297:Male; D051379:Mice; D009154:Mutation; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000378:metabolism; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D016190:Carboplatin; D019001:Nitric Oxide Synthase; D019331:NG-Nitroarginine Methyl Ester
RAS; nitric oxide; nitric oxide synthase; non-small cell lung cancer; preclinical trial