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, Jesper V Olsen

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

2 Citationer (Scopus)
27 Downloads (Pure)

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.

OriginalsprogEngelsk
Artikelnummer2507
TidsskriftNature Communications
Vol/bind12
Udgave nummer1
Antal sider19
ISSN2041-1723
DOI
StatusUdgivet - 2021

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