Mechanism of immunomodulatory drug resistance and novel therapeutic strategies in multiple myeloma

Figures & data

Figure 1. (A) Schematic diagram of crosstalk among key factors after IMiDs act on MM cells. (B) Schematic diagram of signaling pathways involved in IMiD resistance. Abbr. IMiDs, immunomodulatory drugs; MM, multiple myeloma; CRBN, cereblon; GS, glutamine synthetase; ZFP91, zinc-finger 91; IRF4, interferon regulatory factor 4; MMSET, multiple myeloma SET region; C/EBPβ, CCAAT/enhancer binding protein β; PC4, positive coactivator 4; HO-1, heme oxygenase-1; MAPK, mitogen-activated protein kinase; ERK, extracellular signal regulated kinase; Mcl-1, myeloid leukemia 1.

Table 1. Novel strategies for MM treatment associated with IMiDs. Abbr. CBP/EP300, CREB binding protein/adenovirus E1A-related transcriptional coactivating protein; IRF4, interferon regulatory factor 4; HDAC, histone deacetylase; TAK1, TGF-β activated kinase-1; Mcl-1, myeloid leukemia 1; ATO, arsenic trioxide; ATRA, all-trans retinoic acid; BET, bromodomain and extraterminal; PROTAC, proteolysis-targeting chimera.

Drug	Target	Antimyeloma mechanism	Correlation with IMiDs
SGC-CBP30	CBP/EP300	Downregulates IRF4 and MYC expression. Indirectly inhibits IL-6 expression and STAT3 pathway activation	Resensitization
CPI203	BRD4	Downregulates the expression of IRF4, IKZF, and MYC	Synergistic activity
CPI0610	BRD4	Induces G1 cell cycle arrest and caspase-dependent apoptosis. Simultaneously, downregulates the expression of IRF4, IKZF, and MYC	Synergistic activity
JQ1	BRD4	Inhibits the interaction between BRD4 and acetylated proteins. Restricts BRD4 binding to the super enhancer H3K27ac site	Synergistic activity
OTX015	BRD4	Inhibits BRD4 binding to acetylated histones	Synergistic activity
A452	HDAC	Downregulates the expression of IKZF1/3, IRF4, and c-MYC	Synergistic activity
BG45	HDAC	Inhibits activation of the JAK2/STAT3 signaling pathway. Downregulates HO-1 expression	Enhanced sensitivity
NEO2734 or NEO1132	BET and CBP/EP300	Induces obvious G1 phase cell cycle arrest. Reduces the protein levels of IRF4 and c-MYC; as effective as JQ1	Synergistic activity
Selumetinib	MAPK	Inhibits the MAPK/ERK signaling pathway	Resensitization
ATO	MAPK	Upregulates CRBN expression	Enhanced sensitivity
LLZ1640-2	TAK1	Inhibits activation of the NF-κB, p38MAPK/ERK, and STAT3 signaling pathways. Decreases the expression of IRF4, MYC, and Mcl-1	Not reported
ATRA	Wnt pathway	Downregulates β-catenin expression. Decreases the level of total CD44. Reduces the adhesion of MM cells	Enhanced sensitivity
Omacetaxine	Protein translation	Affects both IRF4 and c-MYC	Resensitization
ARV825	BRD4 and CRBN	Downregulates MYC expression	Synergistic activity