MYC is a clinically significant driver of mTOR inhibitor resistance in breast cancer

Jinhyuk Bhin; Julia Yemelyanenko; Xue Chao; Sjoerd Klarenbeek; Mark Opdam; Yuval Malka; Liesbeth Hoekman; Dinja Kruger; Onno Bleijerveld; Chiara S. Brambillasca; Justin Sprengers; Bjørn Siteur; Stefano Annunziato; Matthijs J. van Haren; Nathaniel I. Martin; Marieke van de Ven; Dennis Peters; Reuven Agami; Sabine C. Linn; Epie Boven; Maarten Altelaar; Jos Jonkers; Daniel Zingg; Lodewyk F.A. Wessels

doi:10.1084/jem.20211743

MYC is a clinically significant driver of mTOR inhibitor resistance in breast cancer

Jinhyuk Bhin, Julia Yemelyanenko, Xue Chao, Sjoerd Klarenbeek, Mark Opdam, Yuval Malka, Liesbeth Hoekman, Dinja Kruger, Onno Bleijerveld, Chiara S. Brambillasca, Justin Sprengers, Bjørn Siteur, Stefano Annunziato, Matthijs J. van Haren, Nathaniel I. Martin, Marieke van de Ven, Dennis Peters, Reuven Agami, Sabine C. Linn, Epie BovenMaarten Altelaar, Jos Jonkers^*, Daniel Zingg^*, Lodewyk F.A. Wessels^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Article number	e20211743
Journal	Journal of Experimental Medicine
Volume	220
Issue number	11
DOIs	https://doi.org/10.1084/jem.20211743
Publication status	Published - 29 Aug 2023

Bibliographical note

Publisher Copyright:
© 2023 Bhin et al.

Funding

We thank Catrin Lutz (Netherlands Cancer Institue, Amsterdam, Netherlands) for assisting the xeno-transplantation work of human breast cancer cell lines, Koen Schipper (The Institute of Cancer Research, London, UK) for providing the SIN.LV.SF-Akaluc-T2A-Puro lentiviral vector, Sarah Moser (Netherlands Cancer Institue, Amsterdam, Netherlands) for help with the CRISPR knock-out experiment, Daniel Vis (NetherlandsCancer Institue, Amsterdam, Netherlands) for sharing insights on the Bliss model, and Pierre-René Körner (Netherlands Cancer Institue, Amsterdam, Netherlands) for help with the Ribo-seq analysis. We also thank Anna Dopler and Joana da Silva (Netherlands Cancer Institue, Amsterdam, Netherlands) for their insights and help with the [35S]-methionine radiolabeling assay. We thank the people from the preclinical intervention unit of the Mouse Clinic for Cancer and Ageing at the Netherlands Cancer Institute for their technical support performing the animal experiments. We express gratitude to our colleagues from the Wessels and Jonkers groups for insightful discussions. We thank the Netherlands Cancer Institute genomics core facility, the Research High-Performance Computing facility, the animal pathology facility, the core facility molecular pathology and biobanking, and the proteomics facility for their excellent support. This publication and the underlying study have been made possible partly on the basis of the data that the Hartwig Medical Foundation (Utrecht, Netherlands) and the Center of Personalised Cancer Treatment (Rotterdam, Netherlands) have made available to the study. Research at the Netherlands Cancer Institute is supported by institutional grants from the Dutch Cancer Society and the Dutch Ministry of Health, Welfare and Sport. This work is part of the Oncode Institute, which is partly financed by the Dutch Cancer Society. This work was funded by the Dutch Cancer Society (KWF 2017-61169 to J. Bhin, L.F.A. Wessels, and J. Jonkers; KWF 2020-12894 to D. Zingg, L.F.A. Wessels, and J. Jonkers), the Swiss National Science Foundation (SNF P2ZHP3_175027 to D. Zingg), the Dutch NWO X-omics Initiative (to L. Hoekman and M. Altelaar), and a faculty research grant of Yonsei University College of Medicine (6-2023-0156 and 2023-32-0036). Open Access funding provided by the Netherlands Cancer Institute.

Funders	Funder number
Anna Dopler and Joana da Silva
Hartwig Medical Foundation
NWO X-omics Initiative
Netherlands Cancer Institute
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	P2ZHP3_175027
Ministerie van Volksgezondheid, Welzijn en Sport
KWF Kankerbestrijding
Yonsei University College of Medicine	2023-32-0036, 6-2023-0156
Oncode Institute	KWF 2017-61169, KWF 2020-12894

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1084/jem.20211743Licence: CC BY

jem_20211743Final published version, 9.25 MBLicence: CC BY

Cite this

Bhin, J., Yemelyanenko, J., Chao, X., Klarenbeek, S., Opdam, M., Malka, Y., Hoekman, L., Kruger, D., Bleijerveld, O., Brambillasca, C. S., Sprengers, J., Siteur, B., Annunziato, S., van Haren, M. J., Martin, N. I., van de Ven, M., Peters, D., Agami, R., Linn, S. C., ... Wessels, L. F. A. (2023). MYC is a clinically significant driver of mTOR inhibitor resistance in breast cancer. Journal of Experimental Medicine, 220(11), Article e20211743. https://doi.org/10.1084/jem.20211743

@article{02b8d2c8a16a4d9084a38f21e50ab94b,

title = "MYC is a clinically significant driver of mTOR inhibitor resistance in breast cancer",

abstract = "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.",

author = "Jinhyuk Bhin and Julia Yemelyanenko and Xue Chao and Sjoerd Klarenbeek and Mark Opdam and Yuval Malka and Liesbeth Hoekman and Dinja Kruger and Onno Bleijerveld and Brambillasca, {Chiara S.} and Justin Sprengers and Bj{\o}rn Siteur and Stefano Annunziato and {van Haren}, {Matthijs J.} and Martin, {Nathaniel I.} and {van de Ven}, Marieke and Dennis Peters and Reuven Agami and Linn, {Sabine C.} and Epie Boven and Maarten Altelaar and Jos Jonkers and Daniel Zingg and Wessels, {Lodewyk F.A.}",

note = "Publisher Copyright: {\textcopyright} 2023 Bhin et al.",

year = "2023",

month = aug,

day = "29",

doi = "10.1084/jem.20211743",

language = "English",

volume = "220",

journal = "Journal of Experimental Medicine",

issn = "0022-1007",

publisher = "Rockefeller University Press",

number = "11",

}

Bhin, J, Yemelyanenko, J, Chao, X, Klarenbeek, S, Opdam, M, Malka, Y, Hoekman, L, Kruger, D, Bleijerveld, O, Brambillasca, CS, Sprengers, J, Siteur, B, Annunziato, S, van Haren, MJ, Martin, NI, van de Ven, M, Peters, D, Agami, R, Linn, SC, Boven, E, Altelaar, M, Jonkers, J, Zingg, D & Wessels, LFA 2023, 'MYC is a clinically significant driver of mTOR inhibitor resistance in breast cancer', Journal of Experimental Medicine, vol. 220, no. 11, e20211743. https://doi.org/10.1084/jem.20211743

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 - 2023/8/29

Y1 - 2023/8/29

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 - http://www.scopus.com/inward/record.url?scp=85183403885&partnerID=8YFLogxK

U2 - 10.1084/jem.20211743

DO - 10.1084/jem.20211743

M3 - Article

AN - SCOPUS:85183403885

SN - 0022-1007

VL - 220

JO - Journal of Experimental Medicine

JF - Journal of Experimental Medicine

IS - 11

M1 - e20211743

ER -

MYC is a clinically significant driver of mTOR inhibitor resistance in breast cancer

Abstract

Bibliographical note

Funding

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this