The treatment for small cell lung cancer has not changed much in the past three decades, but this could change with the recent identification of a protein called ASCL1, which plays a major role in the development of this type of cancer.
In the study “ASCL1 and NEUROD1 Reveal Heterogeneity in Pulmonary Neuroendocrine Tumors and Regulate Distinct Genetic Programs,” published in the journal Cell Reports, researchers at UT Southwestern Medical Center have shown that the absence of this protein in the lungs of mice prevented the cancer from forming, suggesting that it may be targeted in patients with small cell lung cancer.
“Our work shows the possibility of developing entirely new types of targeted therapies for small cell lung cancer by focusing on ASCL1,” Dr. John D. Minna, professor and director of the Hamon Center for Therapeutic Oncology Research, and director of the W.A. “Tex” and Deborah Moncrief Jr. Center for Cancer Genetics, said in a press release.
“We used a genetically engineered mouse model that develops human-like small cell lung cancer and identified two regulatory pathways that in turn revealed vulnerabilities in this cancer,” said Dr. Jane E. Johnson, professor of neuroscience and pharmacology, a member of UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center, and the study’s senior author.
Researchers found that the high heterogeneity in small cell lung cancers was caused by differences in the expression of two transcription factors (proteins that regulate gene expression) called ASCL1 and NEUROD1. These proteins induce the expression of specific genes required for tumor cell survival through distinct mechanisms.
This is important because most studies on human small cell lung cancers use cell lines with high levels of NEUROD1 or high levels of ASCL1 interchangeably, which may provide biased results, as researchers showed that these cells behave differently.
The investigators also showed that ASCL1, but not NEUROD1, was required for tumor formation in mouse models of small cell lung cancers, since depleting ASCL1 in a mouse model of small cell lung cancer prevented the cancer from developing. This role of ASCL1 was found to be associated with the expression of several tumor-promoting genes known to be associated with this type of cancer.
The findings suggest that inhibiting ASCL1 in patients with small cell lung cancers who express high levels of this protein may be a promising therapeutic approach.
Small cell lung cancer is a highly aggressive cancer with a very poor prognosis. It is diagnosed in approximately 30,000 people annually in the U.S. alone.