Focusing PI and IMiD Resistance in Multiple Myeloma: Impact of DNA Methylation

Immunomodulatory drugs (IMiDs) and proteasome inhibitors (PI) are backbone agents in the treatment of Multiple Myeloma (MM). However, most patients develop drug resistance over time, with the underlying mechanisms poorly understood. Epigenetic modifications are effective modulatory mechanisms for gene silencing and known to be influenced by the exposure to environmental factors such as drug treatment. Dimopoulous et al. (Molecular Oncology, 2018) recently demonstrated that resistance to IMiDs is also associated with global changes in DNA methylation, although such changes were absent in the annotated promoter region of the CRBN gene. Similarly, DNA methylation of PSMD5 and other regulatory 19S proteasome subunit genes induces PI resistance in various cancer cell lines (Tsvetkov et al. PNAS 2017, eLive 2015).