PXD052949-1

PXD052949 is an original dataset announced via ProteomeXchange.

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

Revision	Datetime	Status	ChangeLog Entry
0	2024-06-09 16:57:38	ID requested
⏵ 1	2024-10-17 05:22:42	announced

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]

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

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

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PRIDE project URI

• PRIDE
  1. PXD052949
     1. Label: PRIDE project
     2. Name: mTORC1-driven protein translation correlates with clinical benefit of capivasertib within a genetically preselected cohort of PIK3CA-altered tumours