PXD041927

PXD041927 is an original dataset announced via ProteomeXchange.

Title	MYC is a clinically significant determinant of mTOR inhibitor resistance in breast cancer
Description	Targeting the PI3K-AKT-mTOR pathway is a promising therapeutic strategy for breast cancer treatment. However, low response rates and the development of acquired resistance to PI3K-AKT-mTOR inhibitors remain major challenges for successful patient treatment. Here, we show that MYC activation is a central and clinically relevant mechanism of resistance to mTOR inhibitors (mTORi) in breast cancer. Multi-omic profiling of mouse invasive lobular carcinoma (ILC) tumors revealed recurrent focal Myc amplification in tumors that acquire resistance to the mTORi AZD8055. The gained MYC activity was significantly associated with biological processes linked to mTORi response. Specifically, MYC counteracted the translation inhibitory effect induced by mTORi by promoting the translation of ribosomal proteins. In vitro and in vivo induction of MYC conferred resistance to AZD8055 as well as the clinically approved mTORi everolimus, both in mouse models of ILC and human breast cancer models. Conversely, AZD8055-resistant ILC cells depended on MYC, as demonstrated by synergistic growth inhibition using 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 determinant of mTORi resistance that may guide the selection of breast cancer patients for mTOR targeted therapies.
HostingRepository	PRIDE
AnnounceDate	2023-05-02
AnnouncementXML	Submission_2023-05-02_09:18:47.064.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	LiesbethHoekman
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2023-05-02 05:44:14	ID requested
⏵ 1	2023-05-02 09:18:47	announced

Dataset with its publication pending

submitter keyword: AZD8055, PI3K-AKT-mTOR signaling pathway, MYC, tumor, mTORi,LC-MSMS, mouse invasive lobular carcinoma, ILC

OnnoBleijerveld
contact affiliation	Proteomics Facility, The Netherlands Cancer Institute, Amsterdam, The Netherlands
contact email	O.bleijerveld@nki.nl
lab head
LiesbethHoekman
contact affiliation	The Netherlands Cancer Institute, Amsterdam, The Netherlands.
contact email	l.hoekman@nki.nl
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/05/PXD041927

PRIDE project URI

• PRIDE
  1. PXD041927
     1. Label: PRIDE project
     2. Name: MYC is a clinically significant determinant of mTOR inhibitor resistance in breast cancer