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Saliba et al. Cancer Drug Resist 2021;4:125-42 I http://dx.doi.org/10.20517/cdr.2020.95 Page 127

Figure 1. Proposed mechanisms of auto-resistance to hypomethylating agents [35] . A: mechanisms related to changes in nucleoside
metabolism: (1) decitabine inhibits thymidylate synthase (TYMS). As a consequence dTTP levels decrease and dCTP levels increase.
This is associated with a (2) decrease in deoxycytidine kinase (DCK), (3) increase in uridine/cytidine kinase 2 (UCK2), and (4) increase
in cytidine deaminase (CDA). Alternatively, azacitidine is metabolized to aza-CDP, which (5) inhibits ribonucleotide reductase (RRM1).
Inhibition of ribonucleotide reductase diminishes the conversion of aza-CDP to aza-dCDP and eventually aza-dCTP, which is capable
of depleting DNMT1. In addition, dCTP levels decrease and, subsequently, (2, 4) DCK and CDA increase while (3) UCK2 decreases,
which in turn decreases the conversion of azacitidine to aza-CMP; B: additional mechanisms of resistance. Decreased expression
of human equilibrative nucleoside transporter (hENT) 1 and 2 is associated with decreased intracellular accumulation of decitabine
and azacitidine. Although not a universal finding, a possible mechanism of resistance in MDS is an increase in carbamoyl-phosphate
synthetase (CAD) expression, resulting in increased synthesis of dCTP, which competes with aza-dCTP for incorporation into DNA.
CMPK: cytosine nucleoside monophosphate kinase; RNR: ribonucleotide reductase; NDPK: nucleoside diphosphate kinase. Figure was
created with BioRender

advances in the treatment of AML, drug resistance continues to be an important clinical problem. As
the armamentarium of therapeutic options continues to expand with agents, like the Nedd8 activating
enzyme (NAE) inhibitors (e.g., pevonedistat) and the mouse double minute 2 homolog protein (MDM2)
inhibitor KRT-232, being added to the HMA/venetoclax backbone, understanding the mechanisms of
action and evolving resistance remains crucial in order to maximize the benefit from emerging drugs
and combinations, identify new potential therapeutic targets, and determine potential prognostic
markers. Hence, we review the individual actions of the HMAs and venetoclax as well as their individual
mechanisms of resistance, and we then focus on potential mechanisms of resistance to the HMA/
venetoclax combination.

HYPOMETHYLATING AGENTS
Mechanisms of action
The HMAs azacitidine and decitabine constitute the backbone of treatment of high-risk myelodysplastic
syndromes (MDS) and chronic myelomonocytic leukemia (CMML) [29-32] . Whether used as single agents
or, more recently, in combination with venetoclax, HMAs have shown clinical activity in patients with
primary, secondary, and relapsed/refractory AML [19,28,33] .

HMAs are pyrimidine analogs of the nucleoside cytidine that showed promising cytostatic activity at
[34]
higher doses in the 1960s . In both azacitidine and decitabine, a nitrogen atom replaces a carbon atom in
position 5 of the pyrimidine ring [Figure 1], but the sugar moiety is deoxyribose in decitabine and ribose
[35]
in azacitidine . There is evidence to support a dual mechanism of action for these agents: (1) a direct
cytotoxic effect at higher doses, where the formation of covalent DNMT-DNA adducts leads to DNA
damage; and (2) DNA hypomethylation and epigenetic modulation at lower doses with subsequent cell
differentiation and tumor suppression [36,37] .