Inhibition of CSF1R and KIT with pexidartinib reduces inflammatory signaling and cell viability in endometriosis

Endocrinology. 2024 Jan 16:bqae003. doi: 10.1210/endocr/bqae003. Online ahead of print.ABSTRACTEndometriosis is a common and debilitating disease, affecting ∼170 million women worldwide. Affected patients have limited therapeutic options such as hormonal suppression or surgical excision of the lesions, though therapies are often not completely curative. Targeting receptor tyrosine-kinases (RTKs) could provide a nonhormonal treatment option for endometriosis. We determined that two RTKs, Macrophage colony stimulating factor receptor (CSF1R) and Mast/stem cell growth factor receptor KIT (KIT), are overexpressed in endometriotic lesions and could be novel nonhormonal therapeutic targets for endometriosis. The kinase activity of CSF1R and KIT is suppressed by pexidartinib, a small molecule inhibitor that was recently approved by the US Food and Drug Administration (FDA). Using immunohistochemistry, we detected CSF1R and KIT in endometriotic tissues obtained from peritoneal lesions, colorectal lesions, and endometriomas. Specifically, we show that KIT is localized to the epithelium of the lesions, while CSF1R is expressed in the stroma and macrophages of the endometriotic lesions. Given the high epithelial expression of CSF1R and KIT, 12Z endometriotic epithelial cells were used to evaluate the efficacy of dual CSF1R and KIT inhibition with pexidartinib. We found that pexidartinib suppressed activation in 12Z cells of JNK, STAT3 and AKT signaling pathways, which control key pro-...
Source: Endocrinology - Category: Endocrinology Authors: Source Type: research