The
Interleukin-23 (IL-23)/IL-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
IL-17. Aside from auto-immunity, this
cytokine has also been linked to
carcinogenesis and polymorphisms in the IL-23R gene are associated with an increased risk for the development of a number of different
cancers. Activation of the
IL-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
IL-17. We have previously identified IL-23A as pro-proliferative and epigenetically regulated in
non-small cell lung cancer (NSCLC). The current study aims to evaluate IL-23R in greater detail in NSCLC. We demonstrate that IL-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 IL-23R. Furthermore,
Apilimod (
STA 5326), a small molecule which blocks the expression of
IL-23 and
IL-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 IL-23/IL-23R axis in this disease.