肿瘤药物的药物敏感性分析揭示子宫平滑肌瘤亚型中的候选治疗靶点

Uterine leiomyomas (ULs) are benign smooth muscle tumors and the most common neoplasms in reproductive aged women affecting up to 80% globally. Although ULs rarely evolve into malignant leiomyosarcomas, they inflict a huge financial and social burden. ULs are known to emerge through a few distinct mutually exclusive genetic driver events, the most common being a hotspot mutation in MED12 and genomic rearrangements of HMGA2 . Currently, ULs are often treated uniformly with surgery as the only curative option. Hormonal therapies can reduce tumor size and symptoms but are limited in efficacy and duration and do not consider the genetic subclass. Therefore, our aim was to characterize drug responses in UL-derived primary cell cultures representing the different tumor subtypes. We established patient-derived primary cell cultures from 5 MED12 and 5 HMGA2 aberrated ULs and their matched normal myometrium. High-throughput drug sensitivity and resistance testing (DSRT) was performed using a comprehensive compound library with 526 clinically approved and investigational cancer drugs. Preliminary results revealed clear differences in drug responses between ULs and matched myometrial cells, including distinct subclass-specific patterns. Principal component analysis and hierarchical clustering of drug response profiles separated ULs from normal tissue, as well as from epithelial ovarian cancer samples previously analyzed using the same compound library and DSRT workflow. Among the 526 tested compounds for UL and myometrium, 280 were considered to have a substantial effect in at least one cell culture sample based on the drug sensitivity score (DSS) threshold set at 80th percentile of responses. Out of these compounds, 18% (N=50) induced stronger effects in tumor cell viability, while 82% (N=230) affected myometrial cells more. At the subclass level, 84% of drugs induced a stronger response in MED12 tumors compared to HMGA2. Notably, compounds inhibiting the insulin-like growth factor 1 receptor (IGF1R) and the phosphoinositide 3-kinase (PI3K), pathways recurrently activated across cancers, produced particularly strong effects in the UL cells with also responses varying between the two subtypes. To date, broad drug discovery efforts for ULs have not been established. Despite their benign nature, ULs share dysregulated signaling pathways with cancers, making these pathways interesting drug targets. While we recognize that cancer drugs often have significant side effects and would not directly be suitable for UL treatment, integrating these cancer drug approaches could enable the development of effective personalized therapies for ULs. Moreover, comparison of drug responses in benign tumors and cancers could help to elucidate how alterations in the same pathways lead to different phenotypic characteristics.