Combination Therapies with Kinase Inhibitors for Acute Myeloid Leukemia Treatment

Abstract

Targeting kinase activity is considered to be an attractive therapeutic strategy to overcome acute myeloid leukemia (AML) since aberrant activation of the kinase pathway plays a pivotal role in leukemogenesis through abnormal cell proliferation and differentiation block. Although clinical trials for kinase modulators as single agents remain scarce, combination therapies are an area of therapeutic interest. In this review, the author summarizes attractive kinase pathways for therapeutic targets and the combination strategies for these pathways. Specifically, the review focuses on combination therapies targeting the FLT3 pathways, as well as PI3K/AKT/mTOR, CDK and CHK1 pathways. From a literature review, combination therapies with the kinase inhibitors appear more promising than monotherapies with individual agents. Therefore, the development of efficient combination therapies with kinase inhibitors may result in effective therapeutic strategies for AML.

Keywords: acute myeloid leukemia; combination; kinase inhibitors; therapy.

Figure 1

Depicted is a schematic presentation of the pathways described in this review. Effects of inhibitors are shown in pink [22,32,35,36,37,38,39,41,43,48,50,51,54,55,57,58,64,67,68,69,70,73,74,82,83,84]. Yellow circles show the molecules frequently targeted by the kinase inhibitors, while gray circles are less frequently targeted, described in the review. MK2, MAPK-activated protein kinases; IRS1, insulin receptor substrate 1; Mnk1/2, MAPK-interacting kinase 1/2; FOXO, Forkhead box O; mTORC1, mTOR complex 1, TCP: tranylcypromine.

Figure 2

Inhibition of CDK9 reduces MCL-1 expression. The depicted figure is a modification from Tibes et al. [75] that was created with BioRender. Blue arrows and red lines are showing effects and inhibitory effects, respectively. Brd4, bromodomain-containing protein 4; CDK, cyclin-dependent kinase; MCL-1, myeloid leukemia-1; RNA pol II, RNA polymerase II.

Figure 3

Differences in the DNA damage checkpoint between normal cells and cancer cells. The ATM-CHK2-p53 pathway is impaired in many cancers [80], and thus CHK1 inhibition is very effective for cancers. The depicted figures are modifications from Smith et al. [80] and Goto et al. [81], with minor modifications created with BioRender. Regulatory pathways in normal cells are shown in blue lines and arrows, whereas these are abrogated in cancer cells, shown in red lines. Pathways shown in gray, are inactivated in cancer cells.