TY - JOUR
T1 - MYC is a clinically significant driver of mTOR inhibitor resistance in breast cancer
AU - Bhin, Jinhyuk
AU - Yemelyanenko, Julia
AU - Chao, Xue
AU - Klarenbeek, Sjoerd
AU - Opdam, Mark
AU - Malka, Yuval
AU - Hoekman, Liesbeth
AU - Kruger, Dinja
AU - Bleijerveld, Onno
AU - Brambillasca, Chiara S.
AU - Sprengers, Justin
AU - Siteur, Bjørn
AU - Annunziato, Stefano
AU - van Haren, Matthijs J.
AU - Martin, Nathaniel I.
AU - van de Ven, Marieke
AU - Peters, Dennis
AU - Agami, Reuven
AU - Linn, Sabine C.
AU - Boven, Epie
AU - Altelaar, Maarten
AU - Jonkers, Jos
AU - Zingg, Daniel
AU - Wessels, Lodewyk F. A.
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85183403885&origin=inward
U2 - 10.1084/jem.20211743
DO - 10.1084/jem.20211743
M3 - Article
C2 - 37642941
SN - 0022-1007
VL - 220
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 11
M1 - e20211743
ER -