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Analysis of Progestin Resistance in Uterine Endometrial Cancer (Abstract ID: 273290)
Abstract   Peer reviewed

Analysis of Progestin Resistance in Uterine Endometrial Cancer (Abstract ID: 273290)

Abby M. Morrison, Kaitriana E. Colling, Miles A. Pufall and Kristina W. Thiel
The Journal of pharmacology and experimental therapeutics, Vol.393(5 Supplement), 104792
05/2026
DOI: 10.1016/j.jpet.2026.104792

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Abstract

The incidence and mortality of uterine endometrial cancer are on the rise, highlighting the need to better understand endometrial cancer pathogenesis and develop more effective therapies. Treatment with progestins is the only non-surgical, conservative treatment option for the increasing number of patients who cannot undergo surgical resection. Although 75% of patients with early-stage, low-grade endometrial cancer initially respond to progestins, up to 40% eventually recur. The mechanisms driving progestin resistance remain poorly understood, in part due to the lack of model systems that recapitulate progestin resistance in patients. Thus, effective strategies to overcome resistance have yet to be clinically implemented. Our objective was to create model systems to understand potential mechanisms of progestin resistance and develop new therapeutic strategies. First, we developed a biorepository of patient-derived organoid (PDO) models from patients who were conservatively managed with progestin therapy and developed resistance. To date, we have generated five PDO models. Using automated kinetic live cell imaging, we examined progestin resistance in vitro by treating models with the same progestin(s) each patient was taking upon developing resistance; most patients received levonorgestrel in combination with either medroxyprogesterone acetate or megestrol acetate. Analysis of growth and apoptosis demonstrated maintenance of therapeutic resistance in vitro. In a subset of models, we identified newer generation hormonal therapies that were effective in resistant PDOs. In parallel, we are establishing progestin-resistant cell lines using the early-stage, low-grade, endometrial cancer cell lines Ishikawa and HCI-EC-23. Initial dose escalation demonstrates progress towards generating progestin-resistant lines without loss of progesterone receptor. Taken together, these results establish new models of progestin resistance for endometrial cancer. Future studies will identify key pathways that drive progestin resistance, thereby enabling development of novel therapeutic opportunities that can be used to potentiate progestin sensitivity.

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