MYC is a clinically significant driver of mTOR inhibitor resistance in breast cancer.
Journal
The Journal of experimental medicine
ISSN: 1540-9538
Titre abrégé: J Exp Med
Pays: United States
ID NLM: 2985109R
Informations de publication
Date de publication:
06 11 2023
06 11 2023
Historique:
received:
17
08
2021
revised:
18
05
2023
accepted:
24
07
2023
medline:
31
8
2023
pubmed:
29
8
2023
entrez:
29
8
2023
Statut:
ppublish
Résumé
Targeting the PI3K-AKT-mTOR pathway is a promising therapeutic strategy for breast cancer treatment. However, low response rates and development of resistance to PI3K-AKT-mTOR inhibitors remain major clinical challenges. Here, we show that MYC activation drives resistance to mTOR inhibitors (mTORi) in breast cancer. Multiomic profiling of mouse invasive lobular carcinoma (ILC) tumors revealed recurrent Myc amplifications in tumors that acquired resistance to the mTORi AZD8055. MYC activation was associated with biological processes linked to mTORi response and counteracted mTORi-induced translation inhibition by promoting translation of ribosomal proteins. In vitro and in vivo induction of MYC conferred mTORi resistance in mouse and human breast cancer models. Conversely, AZD8055-resistant ILC cells depended on MYC, as demonstrated by the synergistic effects of mTORi and MYCi combination treatment. Notably, MYC status was significantly associated with poor response to everolimus therapy in metastatic breast cancer patients. Thus, MYC is a clinically relevant driver of mTORi resistance that may stratify breast cancer patients for mTOR-targeted therapies.
Identifiants
pubmed: 37642941
pii: 276218
doi: 10.1084/jem.20211743
pmc: PMC10465700
pii:
doi:
Substances chimiques
MTOR Inhibitors
0
Phosphatidylinositol 3-Kinases
EC 2.7.1.-
Proto-Oncogene Proteins c-akt
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Swiss National Science Foundation
ID : SNF P2ZHP3_175027
Pays : Switzerland
Informations de copyright
© 2023 Bhin et al.
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