How Pomalidomide Works to Kill Multiple Myeloma

The immunomodulators (thalidomide, lenalidomide and pomalidomide) are a staple class of drugs regularly used in myeloma care. Pomalidomide is often used once patients become resistant to lenalidomide (Revlimid), but how it actually works to kill myeloma has been unclear. Tokyo Institute of Technology, Tokyo Medical University and Saitama Medical University researchers recently published insights into how pomalidomide fights myeloma in Nature Chemical Biology. 

Lenalidomide is known to affect the cereblon pathway, but the Japanese researchers noticed that lenalidomide and pomalidomide affected another protein differently. Lenalidomide caused a small breakdown of a protein called ARID2 and some reductions in the MYC gene, whereas pomalidomide had stronger effects on both. 

The ARID2 protein is a member of the ARID family of DNA-binding proteins. This family of proteins have a role in fetal pattern development, cell lineage gene regulation, cell cycle control, transcriptional regulation and chromatin structure changes. 

The researchers showed that pomalidomide causes the breakdown of a protein called ARID2. ARID2 is involved in the regulation of pomalidomide target genes including MYC. MYC is a well known "master regulator of cell growth in myeloma" (learn more about MYC here and here). Cells that had lower levels of ARID2 after being treated with pomalidomide also had lower levels of MYC. 

When assessing who this is important for and how ARID2 levels can be tested, study author Hiroshi Handa noted: 

"This study found several lines of evidence suggesting that ARID2 expression is associated with a poor prognosis and is higher in patients with relapsed/refractory multiple myeloma, at both the mRNA and protein levels. Analysis of circulating or bone marrow-derived multiple myeloma cells by 
using techniques such as real-time PCR and immunohistochemistry can give valuable information about its expression level."

The researchers believe that these findings suggest that ARID2 is a promising target for overcoming lenalidomide resistance in patients with multiple myeloma. They also believe that ARID2 could be a useful marker to predict overall survival and high levels could identify higher risk patients.