Notch1 Regulates Tumor Formation, Possible Lung Cancer Target

Bench and mouse studies have shown that the Notch1 gene is a crucial contributor to tumorigenesis in non–small-cell lung cancer (NSCLC). It aids tumor initiation by suppressing apoptosis, or programmed cell death, which is regulated by p53. Thus, therapeutic strategies addressing these pathways will depend on patient p53 status.

“The Notch pathway has been implicated in a number of malignancies, with different roles that are cell and tissue-type dependent,” wrote researchers led by Silvia Licciulli, PhD, of the Scripps Research Institute in Jupiter, Florida. “Notch pathway activation has also been correlated to poor prognosis and response to therapy in NSCLC patients.”

First, the researchers used a cell model of adenocarcinoma to test which of the Notch receptors are required for tumor initiation; after observing a “dramatic decrease in cell numbers” only with Notch1 knockdown, they began a mouse study involving inhibition of Notch1. The study’s results were published online ahead of print on August 13 in Cancer Research.

Using a model where K-ras acts as an oncogene and initiates tumor formation, mice that were bred to not have Notch1 function showed an almost uniform distribution of about two cancerous lesions per mouse after 6 weeks, compared with approximately 14 tumors/mouse for those with Notch1 function still remaining. Further, tumor to lung volume ratio was substantially lower in mice without Notch1 function; this ratio was 6% at 6 weeks, 17% at 18 weeks, and 20% at 24 weeks in normal mice, and 4%, 11%, and 9.5%, respectively, in the Notch1-knockdown mice.

“Taken together, our findings indicate that loss of Notch1 significantly reduced K-ras lung tumor initiation and overall tumor burden,” the researchers wrote. Further studies showed that Notch1 knockdown in NSCLC helps induce cell death (which inhibits tumor initiation and growth); this process is mediated by p53, and thus the effects of inhibiting Notch1 require functional p53.

“Our data show that control of survival of lung adenocarcinoma cells by Notch1 requires a functional p53,” they wrote. “Recent data have described a correlation between the levels of activated Notch1 and poor prognosis in a cohort of NSCLC patients, but only in patients with wild type p53,” a group that they wrote represents about half of all NSCLC patients. “Our combined findings demonstrate that p53 status represents a critical determinant in selection of therapeutic strategies for lung adenocarcinoma patients.”

Notch inhibition is still in its infancy as a therapeutic strategy, though some early studies are ongoing, including one phase I/II study on a Notch pathway inhibitor along with chemotherapy in melanoma.