Dataset Information

Multilayered proteomics uncovers Notch/PKC targeting to overcome resistance to Notch inhibition in acute lymphoblastic leukemia

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 toxicity and development of resistance, thus restricting their 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 (PKCδ). 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.

INSTRUMENT(S): Orbitrap Exploris 480, Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Spleen, Cell Suspension Culture, T Cell

DISEASE(S): Acute Leukemia

SUBMITTER: Giulia Franciosa

LAB HEAD: Jesper Velgaard Olsen

PROVIDER: PXD018744 | Pride | 2021-03-08

REPOSITORIES: Pride

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Dataset's files

Source:

			Action	DRS
	20170629_QE5_nLC7_GF_SA_T-ALL_TMT6plexProt_Rep1_F02_170629224619.raw	Raw
	20170629_QE5_nLC7_GF_SA_T-ALL_TMT6plexProt_Rep1_F03_170629233605.raw	Raw
	20170629_QE5_nLC7_GF_SA_T-ALL_TMT6plexProt_Rep1_F04_170630002546.raw	Raw
	20170629_QE5_nLC7_GF_SA_T-ALL_TMT6plexProt_Rep1_F05_170630011524.raw	Raw
	20170629_QE5_nLC7_GF_SA_T-ALL_TMT6plexProt_Rep1_F06_170630020510.raw	Raw

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Publications

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

Franciosa Giulia G Smits Jos G A JGA Minuzzo Sonia S Martinez-Val Ana A Indraccolo Stefano S Olsen Jesper V JV

Nature communications 20210504 1

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, usin ...[more]

PMID: 33947863

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