Identifying and targeting cancer stem cells in leiomyosarcoma: prognostic impact and role to overcome secondary resistance to PI3K/mTOR inhibition.
Adult
Aged
Aldehyde Dehydrogenase 1 Family
/ metabolism
Animals
Cell Line, Tumor
Cohort Studies
Drug Resistance, Neoplasm
Enhancer of Zeste Homolog 2 Protein
/ antagonists & inhibitors
Female
Humans
Imidazoles
/ pharmacology
Leiomyosarcoma
/ drug therapy
Male
Mice
Mice, Inbred NOD
Mice, Knockout
Mice, SCID
Middle Aged
Neoplastic Stem Cells
/ metabolism
Phosphatidylinositol 3-Kinases
/ metabolism
Phosphoinositide-3 Kinase Inhibitors
/ pharmacology
Prognosis
Protein Kinase Inhibitors
/ therapeutic use
Quinolines
/ pharmacology
TOR Serine-Threonine Kinases
/ antagonists & inhibitors
Xenograft Model Antitumor Assays
ALDH1
BEZ235
Cancer stem cell
EZH2
Leiomyosarcoma
Journal
Journal of hematology & oncology
ISSN: 1756-8722
Titre abrégé: J Hematol Oncol
Pays: England
ID NLM: 101468937
Informations de publication
Date de publication:
25 01 2019
25 01 2019
Historique:
received:
15
09
2018
accepted:
27
12
2018
entrez:
27
1
2019
pubmed:
27
1
2019
medline:
11
3
2020
Statut:
epublish
Résumé
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. In this study, we aimed to evaluate the association between CSCs, the outcome of LMS patients, and the resistance to PI3K/mTOR pathway inhibition. We 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. We 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. Altogether, 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.
Sections du résumé
BACKGROUND
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. In this study, we aimed to evaluate the association between CSCs, the outcome of LMS patients, and the resistance to PI3K/mTOR pathway inhibition.
METHODS
We 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.
RESULTS
We 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.
CONCLUSIONS
Altogether, 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.
Identifiants
pubmed: 30683135
doi: 10.1186/s13045-018-0694-1
pii: 10.1186/s13045-018-0694-1
pmc: PMC6347793
doi:
Substances chimiques
Imidazoles
0
Phosphoinositide-3 Kinase Inhibitors
0
Protein Kinase Inhibitors
0
Quinolines
0
Aldehyde Dehydrogenase 1 Family
EC 1.2.1
EZH2 protein, human
EC 2.1.1.43
Enhancer of Zeste Homolog 2 Protein
EC 2.1.1.43
MTOR protein, human
EC 2.7.1.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
dactolisib
RUJ6Z9Y0DT
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
11Commentaires et corrections
Type : ExpressionOfConcernIn
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