An organoid-based drug screening identified a menin-MLL inhibitor for endometrial cancer through regulating the HIF pathway

Tumor organoids recapitulate pathological properties and would serve as an excellent ex vivo model for drug discovery. Here, we performed an unbiased drug screening on drivers-defined tumor organoids from mouse endometrial cancer, the most prevalent gynecological malignancy in human, with a small molecule library targeting epigenetic factors. Among them, menin-MLL inhibitors MI-136 and MI-463 scored. The therapeutic capacity of MI-136 was further validated in tumor organoids in vitro and an orthotopic model in vivo. CRISPR/cas9-mediated mutations of major components of the menin-MLL complex, Men1, Kmt2a and Ash2l, inhibited the growth of tumor organoids, suggesting that the complex was the target of MI-136. Transcriptome analysis showed that the hypoxia-inducible factor (HIF) pathway was the most significantly downregulated pathway by MI-136 treatment. Consistently,Men1,Kmt2a, andAsh2lknockout also repressed the expressions of the HIF target genes. Loss ofHif1aorHif1bpartially phenocopied the inhibition of the menin-MLL complex by MI-136 or mutations in term of tumor organoid growth. Further, we found thatMEN1was upregulated in human endometrial cancers, which were tightly correlated with the expression levels ofHIF1A, and associated with poor prognosis. Importantly, MI-136 also significantly inhibited the growth of endometrial cancer organoids derived from patients. Thus, our study identified MI-136 as a potential inhibitor for endometrial cancer through regulating the HIF pathway, a novel molecular mechanism distinguished from those in AML and prostate cancer.

Automated summary

Tumor organoids were used for drug screening and MI-136 was identified as a potential inhibitor for endometrial cancer by targeting the HIF pathway. The upregulation of MEN1 in human endometrial cancers was found to be closely correlated with the expression levels of HIF1A.