Proteomics of Resistance to Notch1 Inhibition in Acute Lymphoblastic Leukemia Reveals Targetable Kinase Signatures

Overview

Journal Nat Commun

Specialty Biology

Date 2021 May 5

PMID 33947863

Citations 17

Authors

Giulia Franciosa

Jos G A Smits

Sonia Minuzzo

Ana Martinez-Val

Stefano Indraccolo

Jesper V Olsen

Affiliations

Soon will be listed here.

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.

Citing Articles

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Metabolic Profiling as an Approach to Differentiate T-Cell Acute Lymphoblastic Leukemia Cell Lines Belonging to the Same Genetic Subgroup.

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