Scripps Florida Investigators Detail Critical Role of NOTCH1 Gene in Many Lung Cancer Cases
Investigators from the Florida campus of The Scripps Research Institute have shown that NOTCH1, a well-known cancer-causing gene implicated in a number of malignancies, plays a far more critical role in non–small cell lung cancer (NSCLC) than previously thought. These findings establish the gene as a critical regulator of lung cancer tumor growth. The new information could turn out to be vital for the design of potentially new therapeutic strategies for a group of patients who represent almost half of NSCLC cases.
In the study, published online by the journal Cancer Research, the researchers found that the presence of the oncogene NOTCH1 is required for survival of cancer cells. In both cell and animal model studies, disabling NOTCH1 leads to a rise in cancer cell death.
Critical Oncogene
“While NOTCH signaling has emerged as an important target in many types of cancer, current methodologies that target that pathway affect all members of the NOTCH family, and this has been associated with toxicity,” said Joseph L. Kissil, PhD, the Scripps Associate Professor who led the study. “We were able to identify NOTCH1 as the critical oncogene to target, at least in a common form of lung cancer.”
The new findings show that NOTCH1 is required for initial tumor growth, as it represses p53, a well-known tumor-suppressor protein that has been called the genome’s guardian because of its role in preventing mutations. The p53 protein can repair damaged cells or force them to die through apoptosis—programmed cell death.
Using animal models, the study shows that inhibition of NOTCH1 signaling results in a dramatic decrease in initial tumor growth. Moreover, disruption of NOTCH1 induces apoptosis by increasing p53 stability—substantially increasing its biologic half-life, for example.
These findings provide important clinical insights into the correlation between NOTCH1 activity and the poor prognosis of NSCLC patients who carry the nonmutated form of the p53 gene. “If you look at lung cancer patient populations, NOTCH signaling alone isn’t a prognostic indicator, but if you look at p53-positive patients it is,” Kissil said.
The research was supported by the National Institutes of Health (grant number CA124495).
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®.
