Proteomics of resistance to Notch1 inhibition in acute lymphoblastic leukemia reveals targetable kinase signatures

Research output: Contribution to journal › Journal article › Research › peer-review

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Proteomics of resistance to Notch1 inhibition in acute lymphoblastic leukemia reveals targetable kinase signatures. / Franciosa, Giulia; Smits, Jos G A; Minuzzo, Sonia; Martinez-Val, Ana; Indraccolo, Stefano; Olsen, Jesper V.

In: Nature Communications, Vol. 12, No. 1, 2507, 2021.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Franciosa, G, Smits, JGA, Minuzzo, S, Martinez-Val, A, Indraccolo, S & Olsen, JV 2021, 'Proteomics of resistance to Notch1 inhibition in acute lymphoblastic leukemia reveals targetable kinase signatures', Nature Communications, vol. 12, no. 1, 2507. https://doi.org/10.1038/s41467-021-22787-9

APA

Franciosa, G., Smits, J. G. A., Minuzzo, S., Martinez-Val, A., Indraccolo, S., & Olsen, J. V. (2021). Proteomics of resistance to Notch1 inhibition in acute lymphoblastic leukemia reveals targetable kinase signatures. Nature Communications, 12(1), [2507]. https://doi.org/10.1038/s41467-021-22787-9

Vancouver

Franciosa G, Smits JGA, Minuzzo S, Martinez-Val A, Indraccolo S, Olsen JV. Proteomics of resistance to Notch1 inhibition in acute lymphoblastic leukemia reveals targetable kinase signatures. Nature Communications. 2021;12(1). 2507. https://doi.org/10.1038/s41467-021-22787-9

Author

Franciosa, Giulia ; Smits, Jos G A ; Minuzzo, Sonia ; Martinez-Val, Ana ; Indraccolo, Stefano ; Olsen, Jesper V. / Proteomics of resistance to Notch1 inhibition in acute lymphoblastic leukemia reveals targetable kinase signatures. In: Nature Communications. 2021 ; Vol. 12, No. 1.

Bibtex

@article{3f5ae3d6c8284978beaf8b2cc40d0c53,
title = "Proteomics of resistance to Notch1 inhibition in acute lymphoblastic leukemia reveals targetable kinase signatures",
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.",
author = "Giulia Franciosa and Smits, {Jos G A} and Sonia Minuzzo and Ana Martinez-Val and Stefano Indraccolo and Olsen, {Jesper V}",
year = "2021",
doi = "10.1038/s41467-021-22787-9",
language = "English",
volume = "12",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "nature publishing group",
number = "1",

}

RIS

TY - JOUR

T1 - Proteomics of resistance to Notch1 inhibition in acute lymphoblastic leukemia reveals targetable kinase signatures

AU - Franciosa, Giulia

AU - Smits, Jos G A

AU - Minuzzo, Sonia

AU - Martinez-Val, Ana

AU - Indraccolo, Stefano

AU - Olsen, Jesper V

PY - 2021

Y1 - 2021

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-021-22787-9

DO - 10.1038/s41467-021-22787-9

M3 - Journal article

C2 - 33947863

VL - 12

JO - Nature Communications

JF - Nature Communications

SN - 2041-1723

IS - 1

M1 - 2507

ER -

ID: 261514648