Targeting EP300/CBP to Overcome IMiD Resistance in Multiple Myeloma Öffentlichkeit
Lee, Jocelyn (Spring 2025)
Abstract
Multiple Myeloma is a blood cancer of plasma cells in the bone marrow. Immunomodulatory drugs (IMiDs) are a backbone therapy used for myeloma. IMiDs bind the ubiquitin-ligase Cereblon and redirect it to the transcription factors Ikaros (IKZF1) and Aiolos (IKZF3), targeting them for proteasomal degradation. This corresponds with the downregulation of proto-oncogenes such as MYC and IRF4, which leads to myeloma cell death.
While IMiDs initially work well, most myeloma patients become IMiD-resistant. Several studies have suggested mechanisms of resistance to IMiDs, including mutations in Cereblon, but these mutations only occur in some patients. Other studies have identified that transcription factors (ETV4, BATF, BATF2, and BATF3) can maintain MYC and IRF4 expression independently of IKZF1/IKZF3, allowing myeloma to proliferate.
EP300 and CBP are transcriptional co-activators that catalyze the acetylation of histones necessary for MYC and IRF4 expression. Targeting EP300 and CBP has recently been considered an approach to overcoming IMiD resistance. CCS1477 is an EP300/CBP inhibitor in Phase 2 clinical trials and has seen overall response rates of ~70% in myeloma patients, including IMiD-resistant cases. Previous studies have used other EP300/CBP inhibitors in combination with IMiDs and found that the combination downregulated MYC and IRF4 and cell viability. We aim to determine if there is synergy between CCS1477 and the IMiD pomalidomide.
Experiments using varying doses of CCS1477 and pomalidomide in combination and separately were conducted on both IMiD-sensitive and IMiD-resistant cell lines. Combined EP300/CBP inhibition and pomalidomide decreased MYC expression in myeloma cell models. All cell lines had a dose-dependent decrease in viability when CCS1477 and pomalidomide were combined. There was therapeutic synergy in H929 and MM1S across all combination doses and in RPMI8226 and JJN3 at the highest combination doses.
Our results show therapeutic potential for using CCS1477 and pomalidomide in combination to downregulate important oncogenes such as MYC. There was therapeutic synergy in both IMiD-resistant and sensitive cell lines. While there is still much more to understand about the mechanism of synergy between IMiDs and EP300/CBP inhibitors, the combination of CCS1477 and pomalidomide has promising therapeutic uses for myeloma patients.
Table of Contents
INTRODUCTION
Background on Multiple Myeloma
Therapeutic Targeting of Multiple Myeloma
Immunomodulatory Drug Resistance
Targeting Transcriptional Co-Activators
RESEARCH AIMS
METHODS
Cell Lines
Sample preparation
Serial Dilution of CCS1477
Serial Dilution of pomalidomide
Annexin V and Live/Dead Staining and Data Collection
Data Analysis
RESULTS
IMiD and EP300/CBP Inhibitor Modulation of MYC Expression as Measured in JJN3 D11
IMiD-Resistant Cell Lines
IMiD-Sensitive Cell Lines
Results Summary
DISCUSSION
Overview
Results Interpretation
Therapeutic Implications
Limitations
Future Directions
Conclusion
REFERENCES
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