Study Finds Increased Expression of NQO1 in Non–Small Cell Lung Cancer Patients With KRAS Mutations
In smokers with non–small cell lung cancer (NSCLC), the relationship between KRAS mutations and NQO1 may be of future therapeutic value, according to the study findings presented by Yilmaz et al in the International Journal of Environmental Research and Public Health. The researchers suggested that a two-way relationship may exist between KRAS mutational status and oxidative stress.
Oncologists are well aware that cigarette smoking is the main cause of lung cancer. What they also are well aware of is that current treatment approaches have produced various effects. Although treatment with epidermal growth factor receptor (EGFR)-directed therapy has been met with variable success, it may be less effective in patients carrying KRAS mutations. KRAS mutations often result in the loss of GTPase activity and constitutive activation of the downstream proteins, resulting in malignant transformation.
For Yilmaz and colleagues, what was of great interest is the relationship between KRAS mutations and NAD(P)H:quinone oxidoreductase (NQO1) in smokers, which is noted to be overexpressed in lung cancer tumors. In addition, NQO1 is the main activator of quinone-containing alkylating agents such as the mitomycins.
Thus, the investigators set forth to evaluate the possible relationship between KRAS mutations and NQO1 in the hope of gaining greater knowledge of why certain therapies are less effective in smokers with KRAS mutations. They also planned to sequence a panel of clinically relevant proteins in NSCLC patients.
Study Details
The investigators analyzed the medical records of 108 patients with NSCLC with and without KRAS mutations. The five clinical proteins included survivin, DNMT1, DNMT3a, ERK1/2, and c-MET. The latter protein is an oncogene that is vital in the transformation of cells with KRAS mutations.
The median age of patients was 61.0 years. Male gender, a history of smoking, hypertension, and a family history of cancer were present in over 50% of all patients. In total, approximately 48% of all patients were identified as having KRAS mutations.
Certain Proteins Associated With KRAS Mutations
DNMT1, DNMT3a, and ERK1/2 were found to be more evident in patients carrying KRAS mutations. As anticipated, NQO1 was a more frequent finding in patients carrying KRAS mutations. When the KRAS mutational status was ignored, expression of the following proteins was present in over half of the NSCLC patients: NQO1 (67.8%), survivin (75%), DNMT1 (74.6%), and c-MET (68.9%). DNMT3a and ERK1/2 expression were detected in less than half of the patients (43.3% and 46.2%, respectively). The investigators found that expression of c-MET and survivin was not increased in NSCLC patients with KRAS mutations.
Positive NQO1 staining was significantly more frequent in NSCLC patients with mutated rather than with wild-type KRAS mutations (92% vs 48%, P < .001). In addition, positive DNMT1 staining was seen in 57.6% of patients carrying the wild-type KRAS mutation, but 96.2% of the patients carried the KRAS mutation. Positive staining for DNMT1, but negative staining for DNMT3a, was most frequent in NSCLC patients when the KRAS mutational status was ignored.
Closing Thoughts
Despite all efforts, lung cancer has remained the leading cause of cancer deaths worldwide. According to the investigators, one of the reasons for such high mortality is the unavailability of optimized therapeutic options. Such options may emerge with further study into the relationship between oxidative stress and tumorigenesis, possibly initiated by NQO1.
The investigators noted, “We suggest that a two-way relationship that may exist between the KRAS mutational status and oxidative stress may be the starting point for initiating a vicious cycle leading to malignant transformation in NSCLC. Since patients with mutations may utilize quinone-containing alkylating agents more efficiently due to increased NQO1 expression, including KRAS mutational status in future clinical trials may improve success rates.”
Weiqiang Zhao, MD, PhD, of the Department of Pathology, The Ohio State University, Columbus, is the corresponding author of this article in the International Journal of Environmental Research and Public Health.
The study authors reported no potential conflicts of interest.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
