DNA methyltransferase inhibitor exposure-response: Challenges and opportunities

Abstract

Although DNA methyltransferase inhibitors (DNMTis), such as azacitidine and decitabine, are used extensively in the treatment of myelodysplastic syndromes and acute myeloid leukemia, there remain unanswered questions about DNMTi's mechanism of action and predictors of clinical response. Because patients often remain on single-agent DNMTis or DNMTi-containing regimens for several months before knowing whether clinical benefit can be achieved, the development and clinical validation of response-predictive biomarkers represents an important unmet need in oncology. In this review, we will summarize the clinical studies that led to the approval of azacitidine and decitabine, as well as the real-world experience with these drugs. We will then focus on biomarker development for DNMTis-specifically, efforts at determining exposure-response relationships and challenges that remain impacting the broader clinical translation of these methods. We will highlight recent progress in liquid-chromatography tandem mass spectrometry technology that has allowed for the simultaneous measurement of decitabine genomic incorporation and global DNA methylation, which has significant potential as a mechanism-of-action based biomarker in patients on DNMTis. Last, we will cover important research questions that need to be addressed in order to optimize this potential biomarker for clinical use.

FIGURE 1

Membrane transport, metabolism, and mechanism of action of azacitidine and decitabine. Azacitidine and decitabine enter the cells via concentrative nucleoside transporters (SLC 28A or 22A). The equilibrative nucleoside transporter (SLC 29A) mediate the entrance or export depending on the concentration gradient. Once inside the cell, azacitidine (5‐AZA) and decitabine (5‐AZA‐dC) are phosphorylated by a series of kinases, ultimately to 5‐azacytidine triphosphate (5‐AZA‐CTP) and 5‐aza‐2′‐deoxycytidine triphosphate (5‐AZA‐dCTP). Both 5‐AZA and 5‐AZA‐dC undergo deamination by cytidine deaminase (CDA). Ten to 20% of 5‐azacytidine diphosphate (5‐AZA‐CDP) is converted to 5‐aza‐2′‐deoxycytidine diphosphate (5‐AZA‐dCDP) by ribonucleotide reductase. 5‐AZA‐CTP is incorporated into RNA, leading to protein biosynthesis disruption and apoptosis. 5‐AZA‐dCTP is incorporated into DNA, leading to trapping and degradation of DNA methyltransferase (DNMT) enzymes, passive loss of DNA methylation, and ultimately differentiation and expression of tumor suppressive genes (TSGs). Particularly when DNA methyltransferase inhibitors (DNMTis) are given at higher doses, DNA incorporation and trapping of DNMT enzymes can lead to DNA damage and apoptosis. Created with BioRender.com.