PXD026925

PXD026925 is an original dataset announced via ProteomeXchange.

Title	Targeting LCK utilizing a selective inhibitor as a therapeutic approach in Cholangiocarcinoma
Description	There is an unmet need to develop novel, effective medical therapies for cholangiocarcinoma (CCA). The Hippo pathway effector, YAP, is oncogenic in cholangiocarcinoma; however, attempts to therapeutically target YAP in vivo have been unsuccessful thus far. Recently, we described a novel role for the Src-family kinase LCK in activating YAP through tyrosine phosphorylation. This led to the hypothesis that LCK may be a viable therapeutic target in cholangiocarcinoma to regulate YAP activity. NTRC 0652-0 is a novel tyrosine kinase inhibitor with specificity for LCK. NTRC 0652-0 demonstrated selectivity for LCK inhibition in vitro and in cholangiocarcinoma cells. NTRC 0652-0 treatment led to decreased tyrosine phosphorylation of YAP, inhibition of its activity and apoptotic cell death in cholangiocarcinoma cell lines, associated with inhibition of MCL1 expression - consider rephrasing this last part to make the sentence read better. The extent of sensitivity of patient-derived organoids to NTRC 0652-0 correlated with basal YAP tyrosine phosphorylation and suppression of YAP co-transcriptional activity following drug treatment. In a patient-derived xenograft CCA model bearing an FGFR2 fusion, daily oral treatment with NTRC 0652-0 produced stable tumor drug levels, acceptable toxicity, and significantly decreased tumor growth. Overall, a novel LCK inhibitor, NTRC 0652-0, inhibited YAP signaling and demonstrated preclinical efficacy in CCA cell-lines, organoids, and patient derived xenograft models.
HostingRepository	PRIDE
AnnounceDate	2025-05-06
AnnouncementXML	Submission_2025-05-06_09:04:57.193.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Akhilesh Pandey
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	phosphorylated residue
Instrument	Orbitrap Fusion Lumos; Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2021-06-24 23:54:00	ID requested
⏵ 1	2025-05-06 09:04:58	announced

Conboy CB, Yonkus JA, Buckarma EH, Mun DG, Werneburg NW, Watkins RD, Alva-Ruiz R, Tomlinson JL, Guo Y, Wang J, O'Brien D, McCabe CE, Jessen E, Graham RP, Buijsman RC, Vu D, de Man J, Ilyas SI, Truty MJ, Borad M, Pandey A, Gores GJ, Smoot RL, LCK inhibition downregulates YAP activity and is therapeutic in patient-derived models of cholangiocarcinoma. J Hepatol, 78(1):142-152(2023) [pubmed]

10.1016/j.jhep.2022.09.014;

submitter keyword: SILAC, phosphotyrosine, Hippo pathway

Akhilesh Pandey
contact affiliation	Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
contact email	Pandey.Akhilesh@mayo.edu
lab head
Akhilesh Pandey
contact affiliation	Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905
contact email	pandey.akhilesh@mayo.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD026925
     1. Label: PRIDE project
     2. Name: Targeting LCK utilizing a selective inhibitor as a therapeutic approach in Cholangiocarcinoma