1L-23R is epigenetically regulated and modulated by chemotherapy in Non-Small Cell Lung Cancer

The Interleukin-23 (11,23)/11,23R signaling axis is an important inflammatory pathway, involved in the stimulation and regulation of the T helper (Th) 17 lymphocytes, resulting in the production of 11,17 Aside from auto-immunity, this cytokine has also been linked to carcinogenesis and polymorphisms in the II,23R gene are associated with an increased risk for the development of a number of different cancers. Activation of the 11,23 pathway results in the up-regulation of STAT3 and it is thought that the pathological consequences associated with this are in part due to the production of 11,17. We have previously identified II,23A as pro-proliferative and epigenetically regulated in non-small cell lung cancer (NSCLC). The current study aims to evaluate II,23R in greater detail in NSCLC. We demonstrate that II,23R is expressed and epigenetically regulated in NSCLC through histone post-translation modifications and CpG island methylation. In addition, Gemcitabine treatment, a chemotherapy drug used in the treatment of NSCLC, resulted in the up-regulation of the II,23R. Furthermore, Apilimod (STA 5326), a small molecule which blocks the expression of 11,23 and 11,12, reduced the proliferative capacity of NSCLC cells, particularly in the adenocarcinoma (A549) sub-type. Apilimod is currently undergoing investigation in a number of clinical trials for the treatment of auto-immune conditions such as Crohn's disease and Rheumatoid Arthritis. Our results may have implications for treating NSCLC patients with Gemcitabine or epigenetic targeted therapies. However, Apilimod may possibly provide a new treatment avenue for NSCLC patients. Work is currently ongoing to further delineate the 11,23/11,23R axis in this disease.