PXD046700

PXD046700 is an original dataset announced via ProteomeXchange.

Title	CARM1 targeting potentiates IMiD activity: a novel approach to multiple myeloma therapy
Description	Advancements 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.
HostingRepository	PRIDE
AnnounceDate	2025-05-06
AnnouncementXML	Submission_2025-05-06_11:58:08.262.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Eric Fischer
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2023-11-06 06:00:24	ID requested
⏵ 1	2025-05-06 11:58:09	announced

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;

submitter keyword: IKZF1, IKZF3, EZM2302, Aiolos,IMiD, synergy, Ikaros, multiple myeloma

Eric Fischer
contact affiliation	Department 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 email	eric_fischer@dfci.harvard.edu
lab head
Eric Fischer
contact affiliation	Dana-Farber Cancer Institute
contact email	eric_fischer@dfci.harvard.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD046700
     1. Label: PRIDE project
     2. Name: CARM1 targeting potentiates IMiD activity: a novel approach to multiple myeloma therapy