Proteomics of resistance to Notch1 inhibition in acute lymphoblastic leukemia reveals targetable kinase signatures
Giulia Franciosa,
Jos G. A. Smits,
Sonia Minuzzo,
Ana Martinez-Val,
Stefano Indraccolo and
Jesper V. Olsen ()
Additional contact information
Giulia Franciosa: University of Copenhagen
Jos G. A. Smits: University of Copenhagen
Sonia Minuzzo: University of Padova
Ana Martinez-Val: University of Copenhagen
Stefano Indraccolo: University of Padova
Jesper V. Olsen: University of Copenhagen
Nature Communications, 2021, vol. 12, issue 1, 1-19
Abstract:
Abstract Notch1 is a crucial oncogenic driver in T-cell acute lymphoblastic leukemia (T-ALL), making it an attractive therapeutic target. However, the success of targeted therapy using γ-secretase inhibitors (GSIs), small molecules blocking Notch cleavage and subsequent activation, has been limited due to development of resistance, thus restricting its clinical efficacy. Here, we systematically compare GSI resistant and sensitive cell states by quantitative mass spectrometry-based phosphoproteomics, using complementary models of resistance, including T-ALL patient-derived xenografts (PDX) models. Our datasets reveal common mechanisms of GSI resistance, including a distinct kinase signature that involves protein kinase C delta. We demonstrate that the PKC inhibitor sotrastaurin enhances the anti-leukemic activity of GSI in PDX models and completely abrogates the development of acquired GSI resistance in vitro. Overall, we highlight the potential of proteomics to dissect alterations in cellular signaling and identify druggable pathways in cancer.
Date: 2021
References: Add references at CitEc
Citations: View citations in EconPapers (2)
Downloads: (external link)
https://www.nature.com/articles/s41467-021-22787-9 Abstract (text/html)
Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.
Export reference: BibTeX
RIS (EndNote, ProCite, RefMan)
HTML/Text
Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22787-9
Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/
DOI: 10.1038/s41467-021-22787-9
Access Statistics for this article
Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie
More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().