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

Autor:	Sobsey CA; Segal Cancer Proteomics Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada.; Division of Experimental Medicine, McGill University, Montreal, QC, Canada., Froehlich BC; University of Victoria-Genome British Columbia Proteomics Centre, University of Victoria, Victoria, BC, Canada.; Department of Biochemistry and Microbiology, University of Victoria, Victoria, BC, Canada., Mitsa G; Segal Cancer Proteomics Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada.; Division of Experimental Medicine, McGill University, Montreal, QC, Canada., Ibrahim S; Segal Cancer Proteomics Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada.; Division of Experimental Medicine, McGill University, Montreal, QC, Canada., Popp R; MRM Proteomics Inc., Montreal, QC, Canada., Zahedi RP; Segal Cancer Proteomics Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada.; Department of Internal Medicine, University of Manitoba, Winnipeg, MB, Canada.; Manitoba Centre for Proteomics and Systems Biology, Winnipeg, MB, Canada.; Department of Biochemistry and Medical Genetics, University of Manitoba, Winnipeg, MB, Canada.; CancerCare Manitoba Research Institute, Winnipeg, MB, Canada., de Bruin EC; Oncology R&D, AstraZeneca, Cambridge, United Kingdom., Borchers CH; Segal Cancer Proteomics Centre, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada.; Division of Experimental Medicine, McGill University, Montreal, QC, Canada.; Gerald Bronfman Department of Oncology, Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, QC, Canada.; Department of Pathology, McGill University, Montreal, QC, Canada., Batist G; Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC, Canada.; McGill Centre for Translational Research in Cancer, Lady Davis Institute, Montreal, QC, Canada.
Jazyk:	angličtina
Zdroj:	Cancer research communications [Cancer Res Commun] 2024 Aug 01; Vol. 4 (8), pp. 2058-2074.
DOI:	10.1158/2767-9764.CRC-24-0113
Abstrakt:	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 genetically preselected patients and cancer cell lines. We analyzed samples from 16 PIK3CA-mutated patient tumors collected prior to capivasertib monotherapy in the phase I trial. PI3K pathway proteins were precisely quantified with immuno-Matrix-Assisted Laser Desorption/Ionization-mass spectrometry (iMALDI-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 tumors but did not differ between the CB and NCB groups. However, analysis of the global proteome data showed that translational activity was higher in tumors 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 versus -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 preselected patients. Significance: Capivasertib's first-in-class FDA approval demonstrates its promise, yet there remains an opportunity to optimize its use. Our results provide new evidence that proteomics can stratify genetically preselected patients on clinical benefit. Characterization of the same profile in cell lines furnishes additional validation. Among PIK3CA-altered tumors, increased mTORC1-driven translation appears to confer intrinsic resistance. Assessing mTORC1 activation could therefore prove a useful complement to the existing genetic selection strategy for capivasertib. (©2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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