Key Mediators of Relapse Progression in SCLC

Small cell lung cancer (SCLC) is a subtype of lung cancer that arises from the epithelial cells of the lung. It accounts for approximately 15-20% of lung cancer cases. In the United States, over 200,000 people develop this type of lung cancer each year. In Germany alone, there are 7,000 to 8,000 new cases each year. Indeed, the consequences are devastating: only 6 percent of patients survive the deadly disease. This is due to the fact that the disease is characterized by a high cell division rate, early metastatic dissemination, and a rapid growth program. In addition, chemoresistant disease develops in the vast majority of cases.

While mechanisms of resistance have been explored in the context of this disease, there have been no studies that have performed an unbiased global analysis of SCLC cells in a time-dependent manner. Therefore, in a recent study, researchers set out to determine the transcriptional changes that occur in SCLC cells during the period between drug response and recurrence in order to identify the regulators of this process.

Determining key madiators of SCLC relapse progression using RNA-seq

Firstly, they have determined the key mediators of relapse progression. Secondly, they’ve identified a small molecule candidate for delaying relapse of SCLC. They used time-course resolved RNA-sequencing to profile transcriptome changes in SCLC cells in response to cisplatin and etoposide, the standard-of-care treatment for SCLC. As a result, they found that the expression of PEA3 transcription factors ETV4 and ETV5 was transiently upregulated in the surviving fraction of cells. Therefore, they are considered necessary for efficient clonogenic expansion after chemotherapy. They also discovered that a pan-FGFR inhibitor demonstrated efficacy in delaying progression following combination chemotherapy.

We demonstrate transience of the diapause-like state of DTP clones that wanes with increased cellular proliferation as DTPs expand out. We have further demonstrated the importance of both ETV4 and ETV5 expression in promoting efficient clonogenic regrowth in SCLC and identify the kinase inhibitor LY2874455 as a unique pan-FGFR inhibitor that blocks downstream MAPK and PI3K-Akt signaling in SCLC and demonstrates efficacy in curbing SCLC regrowth after cisplatin and etoposide challenge.

To sum up, the study identified molecular targets in the biology of SCLC relapse. Thus, a therapeutic candidate was nominated that could contribute to increased survival of patients with this fatal disease.