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PXD046700

PXD046700 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleCARM1 targeting potentiates IMiD activity: a novel approach to multiple myeloma therapy
DescriptionAdvancements in the treatment of multiple myeloma (MM) have resulted in significant improvement in the survival rate for patients <65, however not for patients >65. There is a particular need for improved therapies for this patient population. The protein arginine methyltransferase, CARM1 (coactivator associated arginine methyltransferase 1), is emerging as a potential cancer therapy target and inhibitors have been developed. MM cell lines are particularly dependent on CARM1 for cell survival. Here, we show that CARM1 targeting through a small molecule drug potentiates immunomodulatory drugs (IMiD) treatment in models of MM, likely through synergistic targeting of Aiolos (IKZF3) and MYC expression. Consistent with this, biorational development of a new molecule, 074, comprised of the CARM1 inhibitor, EZM2302, linked to the IMiD pomalidomide led to more potent killing of MM cells than either compound individually. 074 treatment or the combination of CARM1 knockdown (KD) with pomalidomide led to an upregulation of inflammation and interferon signaling pathways and downregulation of MYC signaling. Importantly, 074 reversed IMiD resistance characterized by MYC protein upregulation and cereblon (CRBN) protein downregulation. Taken together, our results demonstrate that dual CARM1/IKZF3-targeting agents represent a promising novel therapeutic strategy for MM and IMiD-resistant disease.
HostingRepositoryPRIDE
AnnounceDate2025-05-06
AnnouncementXMLSubmission_2025-05-06_11:58:08.262.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterEric Fischer
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListTMT6plex-126 reporter+balance reagent acylated residue; iodoacetamide derivatized residue
InstrumentOrbitrap Fusion Lumos
Dataset History
RevisionDatetimeStatusChangeLog Entry
02023-11-06 06:00:24ID requested
12025-05-06 11:58:09announced
Publication List
Ni W, Garg S, Chowdhury B, Sattler M, Sanchez D, Meng C, Akatsu T, Donovan KA, Qi J, Wang MY, Starnbach CA, Liu X, Guzman MT, Teh WP, Stone R, Griffin JD, Buhrlage S, Weisberg E, Dual CARM1-and IKZF3-targeting: A novel approach to multiple myeloma therapy synergy between CARM1 inhibition and IMiDs. Mol Ther Oncol, 33(1):200952(2025) [pubmed]
10.1016/j.omton.2025.200952;
Keyword List
submitter keyword: IKZF1, IKZF3, EZM2302, Aiolos,IMiD, synergy, Ikaros, multiple myeloma
Contact List
Eric Fischer
contact affiliationDepartment of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA., Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA
contact emaileric_fischer@dfci.harvard.edu
lab head
Eric Fischer
contact affiliationDana-Farber Cancer Institute
contact emaileric_fischer@dfci.harvard.edu
dataset submitter
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