Inhibition of CSF1R and KIT With Pexidartinib Reduces Inflammatory Signaling and Cell Viability in Endometriosis

Dunn, Timothy, Dominique I Cope, Suni Tang, Tirupataiah Sirupangi, Sydney E Parks, Liao, Zian, Zian Liao, Fei Yuan, Chad J Creighton, Ramya P Masand, Linda Alpuing Radilla, Xiaoming Guan, Laura Detti, Diana Monsivais, Martin M. Matzuk
Endocrinology · 2024 · vol. 165(4) · doi:10.1210/endocr/bqae003 · PMID:38227801 · PMC10948355 · W4390903396
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⚙ AI-generated summary by claude@2026-06, 2026-06-08 ⓘ

Pexidartinib, a CSF1R and KIT inhibitor, was found to suppress inflammatory signaling pathways and decrease cell growth and viability in endometriosis.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-08 ⓘ

This study investigated whether receptor tyrosine kinases CSF1R and KIT are overexpressed in human endometriosis lesions and whether pexidartinib (an FDA-approved CSF1R/KIT inhibitor) reduces inflammatory signaling and cell viability. Using analysis of public lesion gene-expression datasets and immunohistochemistry on patient tissue (peritoneal lesions, colorectal lesions, and endometriomas), the authors found KIT localized to lesion epithelium and CSF1R expressed in the stroma and macrophages; they then treated an immortalized endometriosis epithelial cell line (12Z) with pexidartinib. Pexidartinib suppressed activation of JNK, STAT3, and AKT signaling, reduced IL8 and CCND1 mRNA levels, and decreased cell growth and viability, with the authors noting these effects were demonstrated in vitro in a single cell line. This paper is centrally about endometriosis—specifically targeting CSF1R and KIT with pexidartinib to reduce proinflammatory signaling and endometriotic epithelial cell viability.

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Abstract

Endometriosis 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 2 RTKs, macrophage-colony stimulating factor 1 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. 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 proinflammatory and survival networks within the cell. Using quantitative real-time polymerase chain reaction, we determined that pexidartinib suppressed interleukin 8 (IL8) and cyclin D1 (CCND1) expression. Lastly, we demonstrated that pexidartinib decreased cell growth and viability. Overall, these results indicate that pexidartinib-mediated CSF1R and KIT inhibition reduces proinflammatory signaling and cell viability in endometriosis.

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Condition tags

endometriosis

MeSH descriptors

Aminopyridines Aminopyridines Aminopyridines Aminopyridines Aminopyridines Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Pyrroles Pyrroles Pyrroles Pyrroles Pyrroles Cell Survival Cell Survival Cell Survival Cell Survival

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Papers in the corpus that this work cites (lower rings, blue) and that cite this one (upper rings, green). Dot size scales with the paper's in-corpus citation count — bigger dot = more influential within the endo/adeno field. Click a dot to open that paper. [ expand to 2 hops ] — adds papers reached through this work's immediate citers/citees. Heavier; up to 60 extra dots.

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