Abstract
BackgroundLeiomyosarcoma (LMS) is one of the most frequent soft tissue sarcoma subtypes and is characterized by a consistent deregulation of the PI3K/mTOR pathway. Cancer stem cells (CSCs) have been poorly studied in soft tissue sarcomas. In this study, we aimed to evaluate the association between CSCs, the outcome of LMS patients, and the resistance to PI3K/mTOR pathway inhibition.MethodsWe investigated the relationships between aldehyde dehydrogenase 1 (ALDH1) expression, a cancer stem cell marker, and the outcome of LMS patients in two independent cohorts. We assessed the impact of CSCs in resistance to PI3K/mTOR pathway inhibition using LMS cell lines, a xenograft mouse model, and human tumor samples.ResultsWe found that enhanced ALDH1 activity is a hallmark of LMS stem cells and is an independent prognostic factor. We also identified that secondary resistance to PI3K/mTOR pathway inhibition was associated with the expansion of LMS CSCs. Interestingly, we found that EZH2 inhibition, a catalytic component of polycomb repressive complex which plays a critical role in stem cell maintenance, restored sensitivity to PI3K/mTOR pathway inhibition. Importantly, we confirmed the clinical relevance of our findings by analyzing tumor samples from patients who showed secondary resistance after treatment with a PI3Kα inhibitor.ConclusionsAltogether, our findings suggest that CSCs have a strong impact on the outcome of patients with LMS and that combining PI3K/mTOR and EZH2 inhibitors may represent a promising strategy in this setting.
Highlights
Leiomyosarcoma (LMS) is one of the most frequent soft tissue sarcoma subtypes and is characterized by a consistent deregulation of the phosphoinositide 3-kinase (PI3K)/Mammalian target of rapamycin (mTOR) pathway
Studies investigating bone sarcoma cell lines indicated that ALDH1high cells had increased capacity to form spheres and colonies and had significantly greater frequency of tumor-initiating cells
High aldehyde dehydrogenase 1 (ALDH1) expression score was significantly associated with poor metastases-free survival, together with grade 3, and a tumor size of > 10 cm
Summary
Leiomyosarcoma (LMS) is one of the most frequent soft tissue sarcoma subtypes and is characterized by a consistent deregulation of the PI3K/mTOR pathway. Cancer stem cells (CSCs) have been poorly studied in soft tissue sarcomas. We aimed to evaluate the association between CSCs, the outcome of LMS patients, and the resistance to PI3K/mTOR pathway inhibition. Leiomyosarcomas (LMSs) are one of the most frequent histological subtypes of soft tissue sarcomas (15–20%). While several dual PI3K/mTOR inhibitors are under development, this class of drugs suffers from the same major limitation associated with other targeted therapies and traditional chemotherapy drugs in a metastatic disease setting; that is, the duration of any observed clinical benefit is limited, owing to the relatively rapid acquisition of drug resistance. We report here the first study identifying CSCs in LMS, assessing their prognostic impact on the outcome and their role in resistance to therapy, and describe for the first time how an epigenetic intervention may reverse their phenotype and improve response to therapy
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