DNA methyltransferase inhibitors upregulate CD38 protein expression and enhance daratumumab efficacy in multiple myeloma

Abstract

Plasma cells, the malignant cells in multiple myeloma (MM), express high levels of CD38. Daratumumab, the first CD38-targeting therapeutic antibody, is well tolerated and is effective both as monotherapy and in combination regimens. Daratumumab's efficacy in cell lines, in ex vivo patient samples, and in the clinic correlates with expression of CD38 on pretreated myeloma cells [1, 2]. There is a rapid but reversible loss of cell surface CD38 expression on MM cells during daratumumab treatment that favors immune escape/resistance and disease progression [2, 3]. These observations suggest that an increase in CD38 cell surface expression on MM cells could improve daratumumab efficacy and reverse daratumumab resistance. Therefore, efforts are underway to study the regulation of CD38 in MM. Recently, two small molecules that upregulate CD38 expression and work synergistically with daratumumab have been identified: all trans retinoic acid (ATRA) and the histone deacetylase inhibitor Panobinostat [1, 4]. Recent studies have shown that DNA methylation patterns change during MM progression, and clinically aggressive subtypes such as plasma cell leukemias and translocation t(4:14) have hypermethylation [5, 6]. DNA

CD38 Expression by Myeloma Cells and Its Role in the Context of Bone Marrow Microenvironment: Modulation by Therapeutic Agents

“…The same effect has been found with lenalidomide and pomalidomide. More recently, it has been reported that DNMTi as AZA or DEC also increase CD38 expression by MM cells [58]. Figure 1 summarizes the main mechanisms involved in the modulation of CD38 expression in MM cells and in the BM microenvironment by different molecules with a possible therapeutic impact.…”

“…Next, by using immortalized NK transgenic cell line, the authors showed a significant increase in DARA-mediated-ADCC against MM cells pre-treated with DNMTi as compared to not-treated cells [58]. The mechanism behind the AZA-mediated upregulation of CD38 expression by MM cells involved TNF-α signaling as demonstrated by the abrogation of DNMTi effect in the presence of neutralizing TNF-α antibody [58].…”

“…Moreover, analysis of different independent MM datasets showed an inverse relationship between normal PCs and malignant MM cells in terms of CD38 methylation and gene expression status [58]. Accordingly, it has been recently demonstrated by flow-cytometry that DNA methyltrasnferase inhibitors (DNMTi), as azacytidine (AZA) and decitabine (DEC), increase CD38 expression on a panel of human MM cell lines, without affecting cell viability [58]. Furthermore, the combination of AZA or DEC with ATRA, significantly increased surface CD38 expression as compared with the treatment with the single drugs [58].…”

“…CD38 was identified as a differential methylating region in MM patients with a negative correlation between DNA methylation and gene expression. Moreover, analysis of different independent MM datasets showed an inverse relationship between normal PCs and malignant MM cells in terms of CD38 methylation and gene expression status [58]. Accordingly, it has been recently demonstrated by flow-cytometry that DNA methyltrasnferase inhibitors (DNMTi), as azacytidine (AZA) and decitabine (DEC), increase CD38 expression on a panel of human MM cell lines, without affecting cell viability [58].…”

“…Accordingly, it has been recently demonstrated by flow-cytometry that DNA methyltrasnferase inhibitors (DNMTi), as azacytidine (AZA) and decitabine (DEC), increase CD38 expression on a panel of human MM cell lines, without affecting cell viability [58]. Furthermore, the combination of AZA or DEC with ATRA, significantly increased surface CD38 expression as compared with the treatment with the single drugs [58]. Next, by using immortalized NK transgenic cell line, the authors showed a significant increase in DARA-mediated-ADCC against MM cells pre-treated with DNMTi as compared to not-treated cells [58].…”