Investigating BMP signaling as a therapeutic vulnerability in endometrial cancer

Introduction: Endometrial cancer (EC) is the sixth most common malignancy in women worldwide, with nearly 400,000 new cases annually. Aggressive EC subtypes are associated with poor prognosis, highlighting the urgent need for mechanism-based therapies. Emerging evidence implicates Bone Morphogenetic Protein (BMP) signaling as a driver of EC progression. Approximately 5% of EC tumors harbor ACVR1(R206H) gain-of-function mutations, which overactivate BMP signaling. Our goal is to define the prevalence, sources, and functional consequences of BMP activation in EC and assess whether pharmacologic inhibition suppresses tumor growth. Methods: Phospho-SMAD1/5/8 (pSMAD) levels were quantified in EC tumors and normal endometrium to assess BMP pathway activation. Genomic and transcriptomic datasets were analyzed to identify ACVR1 mutations and BMP ligand expression associated with patient survival. Functional studies were conducted in multiple EC cell lines using the pan-BMP inhibitor DMH1. pSMAD was measured by western blot, downstream BMP target gene transcription (ID1/ID3) was assessed by qPCR, and cell viability was evaluated to determine the effect of BMP inhibition on tumor cell survival and proliferation. Results: pSMAD levels were elevated in over half of EC tumors compared with low-to-moderate levels in normal endometrium. High expression of BMP ligands GDF6 and BMP7 correlated with poor overall survival. DMH1 selectively reduced pSMAD without affecting total SMAD, downregulated ID1 and ID3, and decreased viability in Ishikawa, HEC1A, and AN3CA cells within 24 hours, demonstrating that BMP signaling is required to sustain tumor growth and proliferation. Conclusions: BMP signaling is recurrently activated in EC through receptor mutation and ligand overexpression, promoting aggressive tumor behavior. Pharmacologic inhibition reverses downstream transcriptional activity and suppresses tumor cell viability, establishing BMP signaling as an actionable therapeutic vulnerability. These findings support the development of BMP-directed strategies to improve clinical outcomes in patients with endometrial cancer.