Fourneaux B, et al. - Researchers assessed the link between cancer stem cells (CSCs), the outcome of leiomyosarcoma (LMS) patients, and the resistance to PI3K/mTOR pathway inhibition using two independent cohorts and LMS cell lines, a xenograft mouse model, and human tumor samples. The links between aldehyde dehydrogenase 1 (ALDH1) expression, a cancer stem cell marker, and the outcome of LMS patients was investigated. Enhanced ALDH1 activity was identified as a hallmark of LMS stem cells and displayed ability as an independent prognostic factor. Expansion of LMS CSCs was noted in relation to secondary resistance to PI3K/mTOR pathway inhibition. Sensitivity to PI3K/mTOR pathway inhibition was restored by EZH2 (Enhancer of zeste homolog 2) inhibition, a catalytic component of polycomb repressive complex which plays a critical role in stem cell maintenance. Analysis of tumor samples from patients who demonstrated secondary resistance after treatment with a PI3Kα inhibitor corroborated the clinical relevance of these findings. Overall, a robust influence of CSCs on LMS prognosis was seen. A promising strategy may involve combining PI3K/mTOR and EZH2 inhibitors.