PXD030214

PXD030214 is an original dataset announced via ProteomeXchange.

Title	Synergistic targeting of DNA-PK and KIT signaling pathways in KIT mutant acute myeloid leukemia
Description	Acute Myeloid Leukemia (AML) is the most common and aggressive form of acute leukemia, with a 5-year survival rate of just 24%. Over a third of all AML patients harbor activating mutations in kinases, such as the receptor tyrosine kinases FLT3 and KIT. FLT3 and KIT mutations are associated with poor clinical outcomes and lower remission rates in response to standard-of-care chemotherapy. We have recently identified that the core kinase of the non-homologous end joining DNA repair pathway, DNA-PK, is activated downstream of FLT3; and targeting DNA-PK sensitized FLT3-mutant AML cells to standard-of-care therapies. Herein, we investigated DNA-PK as a possible therapeutic vulnerability in KIT mutant AML, using isogenic FDC-P1 myeloid progenitor cell lines transduced with an empty vector or oncogenic mutant KIT (V560G, D816V). Targeted quantitative phosphoproteomic profiling identified phosphorylation of DNA-PK at threonine 2599 in KIT mutant cells, indicative of DNA-PK activation. Accordingly, proliferation assays revealed that KIT mutant FDC-P1 cells were more sensitive to the DNA-PK inhibitors M3814 or NU7441, compared to empty vector controls. DNA-PK inhibition combined with inhibition of KIT signaling via using the kinase inhibitors dasatinib or ibrutinib, or the protein phosphatase 2A activators FTY720 or AAL(S), led to synergistic cell death. Discovery phosphoproteomic analysis of KIT-D816V cells revealed that dasatinib single-agent treatment inhibited ERK1 activity, and M3814 single-agent treatment inhibited Akt/mTOR activity. The combination of dasatinib and M3814 treatment inhibited both ERK/MAPK and Akt/mTOR activity, and induced synergistic inhibition of phosphorylation of transcription regulators including MYC and MYB. This study provides insight into the oncogenic pathways regulated by DNA-PK beyond its canonical role in DNA repair, and demonstrates that DNA-PK is a promising novel therapeutic target for KIT mutant cancers.
HostingRepository	PanoramaPublic
AnnounceDate	2023-01-26
AnnouncementXML	Submission_2023-01-26_11:34:21.983.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Heather Murray
SpeciesList	scientific name: Mus musculus; NCBI TaxID: 10090;
ModificationList	Phospho; Oxidation
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2021-12-06 08:30:53	ID requested
⏵ 1	2023-01-26 11:34:23	announced

Murray HC, Miller K, Brzozowski JS, Kahl RGS, Smith ND, Humphrey SJ, Dun MD, Verrills NM, Synergistic Targeting of DNA-PK and KIT Signaling Pathways in KIT Mutant Acute Myeloid Leukemia. Mol Cell Proteomics, 22(3):100503(2023) [pubmed]

submitter keyword: Phosphoproteomics, AML, KIT

Nikki Verrills
contact affiliation	School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle
contact email	Nikki.Verrills@newcastle.edu.au
lab head
Heather Murray
contact affiliation	School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle
contact email	heather.murray@newcastle.edu.au
dataset submitter

Panorama Public dataset URI