PXD023231

PXD023231 is an original dataset announced via ProteomeXchange.

Title	Activity of the novel BTK inhibitor TG-1701 is associated with the disruption of the Ikaros signaling pathway in responder B-NHL patients and with sensitization to anti-CD20 therapy in B-NHL xenografts
Description	Covalent Bruton's tyrosine kinase inhibitors (BTKis) have transformed the treatment of B-cell non-Hodgkin lymphoma (B-NHL), including chronic lymphocytic leukemia (CLL) and mantle cell lymphoma (MCL), but their activity has been limited by off-target toxicity and acquired drug resistance. TG-1701 is a novel irreversible and highly specific BTKi being presently under study in a phase 1 clinical trial in patients with relapsed/refractory B-NHL alone and in combination with ublituximab, a CD20 antibody, and umbralisib, a dual PI3Kδ and CK1ε inhibitor. Here we show, for the first time that phosphoproteomic analysis of CLL patients receiving a BTKi (TG-1701) led to a non-supervised clustering that matched the clinical outcomes and separated a group of “responders” from a group of “non-responders”. This clustering was based on a selected list of 96 phosphosites, with Ikaros-Ser442/445 phosphorylation as a potential marker for TG-1701 efficacy. RNA-seq analysis followed by qPCR and western blot validation further revealed that TG-1701 treatment blunted the Ikaros gene signature only in responder patients, as well as in BTKi-sensitive, but not BTKi-insensitive, B-NHL cell lines and xenografts. Importantly, and in contrast with ibrutinib, TG-1701 did not impair FcγR-driven antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADCP) triggered by the anti-CD20 antibodies rituximab and ublituximab in a multicellular MCL co-culture system. In addition, TG-1701 cooperated with ublituximab coupled to umbralisib (also referred as the U2 regimen) in reducing the tumor growth in both ibrutinib-sensitive and ibrutinib-insensitive mouse models of MCL. Altogether, these data validate phosphoproteomic as a broken thread to omics analysis in the clinic and support the use of TG-1701-U2 combination in R/R B-NHL patients, irrespective of prior response to ibrutinib.
HostingRepository	PRIDE
AnnounceDate	2021-09-22
AnnouncementXML	Submission_2021-09-22_07:01:57.617.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Joan Josep Bech-Serra
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2020-12-18 08:18:27	ID requested
⏵ 1	2021-09-22 07:01:57	announced

Dataset with its publication pending

submitter keyword: BTK, Ikaros, B-NHL, TG-1701, xenografts, phosphoproteomics, TMT, MaxQuant

Gael Roue
contact affiliation	Lymphoma Translational Group, Josep Carreras Leukaemia Research Institute, Badalona, Spain
contact email	groue@carrerasresearch.org
lab head
Joan Josep Bech-Serra
contact affiliation	Proteomics Unit - Josep Carreras Leukaemia Research Institute
contact email	jbech@carrerasresearch.org
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD023231
     1. Label: PRIDE project
     2. Name: Activity of the novel BTK inhibitor TG-1701 is associated with the disruption of the Ikaros signaling pathway in responder B-NHL patients and with sensitization to anti-CD20 therapy in B-NHL xenografts