PXD052949 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | mTORC1-driven protein translation correlates with clinical benefit of capivasertib within a genetically preselected cohort of PIK3CA-altered tumours |
Description | Capivasertib is a potent selective inhibitor of AKT. It was recently FDA-approved in combination with fulvestrant to treat HR+, HER2-negative breast cancers with certain genetic alteration(s) activating the PI3K pathway. In Phase I trials, heavily pre-treated patients with tumours selected for activating PI3K pathway mutations treated with capivasertib monotherapy demonstrated objective response rates of <30%. We investigated the proteomic profile associated with capivasertib response in genetically pre-selected patients and cancer cell lines. We analyzed samples from 16 PIK3CA-mutated patient tumours collected prior to capivasertib monotherapy in the Phase I trial. PI3K pathway proteins were precisely quantified with immuno-MALDI-MS. Global proteomic profiles were also obtained. Patients were classified according to response to capivasertib monotherapy: “clinical benefit (CB)” (≥12 weeks without progression, n=7) or “no clinical benefit (NCB)” (progression in <12 weeks, n=9). Proteins that differed between the patient groups were subsequently quantified in AKT1- or PIK3CA-altered breast cancer cell lines with varying capivasertib sensitivity. The measured concentrations of AKT1 and AKT2 varied among the PIK3CA-mutated tumours but did not differ between the CB and NCB groups. However, analysis of the global proteome data showed that translational activity was higher in tumours of the NCB vs. CB group. When reproducibly quantified by validated LC-MRM-MS assays, the same proteins of interest similarly distinguished between capivasertib-sensitive vs. -resistant cell lines. The results provide further evidence that increased mTORC1-driven translation functions as a mechanism of resistance to capivasertib monotherapy. Protein concentrations may offer additional insights for patient selection for capivasertib, even among genetically pre-selected patients. |
HostingRepository | PRIDE |
AnnounceDate | 2024-10-17 |
AnnouncementXML | Submission_2024-10-17_05:22:41.803.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | Constance Sobsey |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | acetylated residue |
Instrument | LTQ Orbitrap Elite |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2024-06-09 16:57:38 | ID requested | |
⏵ 1 | 2024-10-17 05:22:42 | announced | |
Publication List
10.1158/2767-9764.crc-24-0113; |
Sobsey CA, Froehlich BC, Mitsa G, Ibrahim S, Popp R, Zahedi RP, de Bruin EC, Borchers CH, Batist G, mTORC1-Driven Protein Translation Correlates with Clinical Benefit of Capivasertib within a Genetically Preselected Cohort of PIK3CA-Altered Tumors. Cancer Res Commun, 4(8):2058-2074(2024) [pubmed] |
Keyword List
submitter keyword: PI3K/AKT/mTOR signaling pathway in cancer |
tyrosine kinase inhibitors |
capivasertib (AZD5363) |
precision medicine |
genetic mutations |
breast cancer |
gynecological cancer |
targeted proteomics |
global proteomics |
translational control |
Contact List
Christoph Borchers |
contact affiliation | Segal Cancer Proteomics Centre |
contact email | christoph.borchers@mcgill.ca |
lab head | |
Constance Sobsey |
contact affiliation | McGill University |
contact email | constance.sobsey@mail.mcgill.ca |
dataset submitter | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD052949
- Label: PRIDE project
- Name: mTORC1-driven protein translation correlates with clinical benefit of capivasertib within a genetically preselected cohort of PIK3CA-altered tumours