Pituitary neuroendocrine tumors (PitNETs) are the most common type of benign tumors found in the saddle area. Prolactinoma accounts for 30-50% of all PitNETs(Chanson and Maiter). Pharmacotherapy is the primary approach for managing prolactinomas, with dopamine agonists (DAs) being the foremost therapy for almost all cases of prolactinomas. Prolactinomas sometimes exhibit resistance to treatment with DAs. The estimated incidence of DA resistance is 10% for cabergoline and around 20-30% for bromocriptine (Fukuhara et al., 2022a). DA resistance is characterized by the failure to achieve normalization of serum PRL levels and a reduction in tumor size by 50% or more after 3-6 months of treatment with the maximum tolerated dose of DA per week(Dogansen et al., 2018; Gonzaga et al., 2018; Maiter, 2019; Molitch, 2014). DA resistance is more common in macroprolactinomas, invasive tumors, and male patients(Fukuhara et al., 2022b). Surgery is an effective way to treat patients with DA-resistant(Vroonen et al., 2019). The therapeutic effect of surgery is related to the size and invasiveness of the tumor(Cai et al., 2016). However, it is uncommon for straightforward surgical procedures to effectively cure large prolactinomas. For the majority of patients, hormone relief is not achieved after surgery, and more than 50% of patients experience tumor recurrence or regrowth after surgery(Liu et al., 2018). Therefore, further research is still needed on the mechanisms of drug resistance to clarify more effective treatments.

The reduction of dopamine receptor density in prolactinoma cells is considered to be the primary potential mechanism of DA resistance(Cai et al., 2016; Lasolle et al., 2019). Studies have also shown that increased expression of estrogen receptors alpha (ERα) and beta (ER-β) is associated with tumor resistance(Lasolle et al., 2020; Souteiro and Karavitaki, 2020; Su et al., 2019). The overexpression of VEGF, EGF, increased fibrosis, and disruption of the TGF-β1 pathway are also considered possible mechanisms of DA resistance(Lasolle et al., 2020; Maiter, 2019). Therefore, the biological mechanisms of resistance are complex and unclear.

With the rise of precision medicine in oncology, personalized treatment plans for tumor patients have become a highly effective approach. Patient-derived tumor organoids (PDOs) are generated from a patient’s tumor tissue and cultured in 3D using stromal gels as the extracellular matrix. They accurately mimic the biological behavior of human tumors and can predict the efficacy of drug therapy, making them excellent preclinical models(Chen et al., 2023; Corrò et al., 2020; de Souza, 2018; Drost and Clevers, 2018; Qin et al., 2023). Based on the research findings, tumor organoids models have been successfully established in various cancers such as liver cancer(Broutier et al., 2017), gastric cancer(Seidlitz et al., 2021), pancreatic cancer(Boj et al., 2015), colon cancer(Teijeira et al., 2022), breast cancer(Roelofs et al., 2019), and chordoma(Al Shihabi et al., 2022), and effective drug screening has been conducted, leading to promising outcomes. There are currently no prolactinoma organoid models that are resistant to dopamine agonists. Our recent research has found that human prolactinoma organoid cultures can grow long-term in vitro and retain the biological functionality of prolactinomas. We have successfully established and characterized 8 dopamine-resistant prolactinoma organoids. This study employed prolactinoma organoids to conduct large-scale screening of 180 anti-tumor drugs and to validate the effectiveness of the drugs through functional experiments. Furthermore, the study analyzed the drug targets and combined genomics sequencing data to reveal the mechanism of prolactinoma resistance and identified new effective drugs to treat resistant prolactinoma.