After decades of inactivity, there is finally some movement in the treatment strategy of AML patients. As opposed to the standard Cytarabine+Daunorubicin combination, the newly approved drugs are specifically targeting proteins and pathways that are all involved in survival signaling of AML cells (rather than induction of apoptosis by disrupting DNA replication). Thanks to the increased knowledge of AML biology and survival pathways, we now have much more information and insights into how AML cells can survive and propagate. For this review, we wanted to look into these new findings and extract those with promising preclinical potencies to help fight the battle against AML. After searching the current literature, we found that the pathways involved in AML survival could be categorized into some of the major hallmarks of cancer. These included immune evasion, differentiation impairment, and metabolic reprogramming. An additional category we wanted to add was drug resistance, which is very relevant in AML. A subset of the targets has moved forward from clinical trials and has even made it to approval. However, in this review, we wanted to focus on the newcomers since there are already recently published reviews about the successful candidates in the clinical trials (Figure 1).

The targets that we cover in this review are SAMHD1, members of the sphingosine metabolism pathway (AC and SK), LILRB4, PARP1, NOX, PFKFB3, and DHODH (Figure 1). An interesting theme that arose during the research for this review was how some of these pathways seem to overlap and how combining treatments against several targets could benefit a wider group of patients. For example, PARP inhibitors, which have already been evaluated for tolerance in clinical trials for other diseases, have shown promising synergistic effects combined with chemotherapeutics that are already in clinical use against AML, such as FLT3 inhibitors and Daunorubicin (1,2). Additionally, combined targeting of the pentose phosphate pathway and glycolysis via TIGAR and PFKFB3, respectively, could cut-off the energy supply of AML blasts. This is because inhibiting TIGAR makes the blasts more sensitive to PFKFB3 (3). Thereby, targeting them together could more efficiently prevent the propagation of the leukemic blasts by taking away their flexibility to switch between the two energy production pathways. Like this, several studies mentioned in this review have revealed similar situations where inhibiting one pathway increases the sensitivity of the blasts to another.

One of the main take-home messages from this review is the need for more combination trials and a more interdisciplinary view of AML survival pathways. It could have occurred that treatments targeting some pathways failed to enter the clinics only due to low efficacy as monotherapy. As highlighted several times in this review, the inhibition of individual targets, even though not sufficient on its own, could very well increase the sensitivity of the leukemic blasts to inhibition of other related pathways or targets, as exemplified by PFKFB3 and TIGAR inhibition. With more target combinations in clinical trials, perhaps more treatment options, previously rejected due to ineffective monotherapy, could enter the AML treatment scheme and benefit more patients.

Figure 1: AML survival pathways and targets discussed in the review.

1. Molenaar RJ, Radivoyevitch T, Nagata Y, Khurshed M, Przychodzen B, Makishima H, et al. Idh1/2 mutations sensitize acute myeloid leukemia to parp inhibition and this is reversed by idh1/2-mutant inhibitors. Clin Cancer Res. 2018 Apr 1;24(7):1705–15.
2. Dellomo AJ, Baer MR, Rassool F V. Partnering with PARP inhibitors in acute myeloid leukemia with FLT3-ITD. Vol. 454, Cancer Letters. Elsevier Ireland Ltd; 2019. p. 171–8.
3. Qian S, Li J, Hong M, Zhu Y, Zhao H, Xie Y, et al. TIGAR cooperated with glycolysis to inhibit the apoptosis of leukemia cells and associated with poor prognosis in patients with cytogenetically normal acute myeloid leukemia. J Hematol Oncol. 2016 Dec 25;9(1):128.