Dataset Information

MTORC1-driven protein translation correlates with clinical benefit of capivasertib within a genetically preselected cohort of PIK3CA-altered tumours

ABSTRACT: 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.

INSTRUMENT(S): LTQ Orbitrap Elite

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Malignant Cell, Breast Cancer Cell, Ovary Cancer Cell

DISEASE(S): Female Reproductive Organ Cancer,Breast Cancer

SUBMITTER: Constance Sobsey

LAB HEAD: Christoph Borchers

PROVIDER: PXD052949 | Pride | 2024-10-17

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	CS_AKT_supernatants_new_LFQ.msf	Msf
	CS_AKT_supernatants_new_LFQ.msfView	Msf
	CS_AKT_supernatants_new_LFQ.pdResult	Other
	CS_AKT_supernatants_new_LFQ.pdResultView	Other
	CS_AKT_supernatants_new_LFQ.xlsx	Xlsx

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mTORC1-Driven Protein Translation Correlates with Clinical Benefit of Capivasertib within a Genetically Preselected Cohort of PIK3CA-Altered Tumors.

Sobsey Constance A CA Froehlich Bjoern C BC Mitsa Georgia G Ibrahim Sahar S Popp Robert R Zahedi Rene P RP de Bruin Elza C EC Borchers Christoph H CH Batist Gerald G

Cancer research communications 20240801 8

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 pretreated patients with tumors 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 genetical ...[more]

PMID: 38954770

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