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Review
. 2017 Mar 29;10(1):77.
doi: 10.1186/s13045-017-0443-x.

The cell cycle checkpoint inhibitors in the treatment of leukemias

A Ghelli Luserna di Rora'  1 , I Iacobucci  2   3 , G Martinelli  2
Affiliations
Review

The cell cycle checkpoint inhibitors in the treatment of leukemias

A Ghelli Luserna di Rora' et al. J Hematol Oncol. .

Abstract

The inhibition of the DNA damage response (DDR) pathway in the treatment of cancers has recently reached an exciting stage with several cell cycle checkpoint inhibitors that are now being tested in several clinical trials in cancer patients. Although the great amount of pre-clinical and clinical data are from the solid tumor experience, only few studies have been done on leukemias using specific cell cycle checkpoint inhibitors. This review aims to summarize the most recent data found on the biological mechanisms of the response to DNA damages highlighting the role of the different elements of the DDR pathway in normal and cancer cells and focusing on the main genetic alteration or aberrant gene expression that has been found on acute and chronic leukemias. This review, for the first time, outlines the most important pre-clinical and clinical data available on the efficacy of cell cycle checkpoint inhibitors in single agent and in combination with different agents normally used for the treatment of acute and chronic leukemias.

Keywords: Acute lymphoblastic leukemia; Acute myeloid leukemia; Checkpoint kinase inhibitor; Chronic lymphocytic leukemia; Chronic myeloid leukemia; DNA damage response.

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Figures

Fig. 1
Fig. 1
Schematic representation of the DNA damage response (DDR) pathway. DNA damages are sensed and repaired in multi-protein complexes. Signaling caused by this damage results in the activation of different mediators of the damage response and then results in cell cycle arrest and a choice between repair or progression to apoptosis
Fig. 2
Fig. 2
DNA damages sensor and mediators in the response to DSBs and SSBs. DNA damages trigger the recruitment of specific damage sensor protein complexes. On one hand, the MRN (MRE11–RAD50–NBS1) complex is required for the activation of ataxia-telangiectasia mutated (ATM) in response to double-strand breaks (DSBs). On the other hand, the ATM- and Rad3-related (ATR)-interacting protein (ATRIP) complex, formed by ATR-ATRIP-9-1-1 complex, is recruited to sites of single-strand breaks and activates ATR. The activation of ATM and ATR promotes respectively the activation of two different effectors, CHK2 and CHK1. Although currently, the activator of WEE1 is unknown, it is believed that CHK1 promotes WEE1 activation
Fig. 3
Fig. 3
The DDR pathway in cancer cells. The high proliferation rate induced by different oncogenes (MYC or BCR-ABL1) can led to the so called replicative stress which is a negative signal for proliferation. In order to sustain the replicative stress and continue to proliferate, leukemic cells need to up-regulate different key elements of the DDR pathway, like CHK1. The two most important consequences of DDR elements up-regulation are (1) genetic instability due to the increment of tolerable level of DNA damages and (2) resistance to DNA damaging agents, such as chemotherapies, due to the up-regulation of the mechanisms involved in the DNA repair
Fig. 4
Fig. 4
Schematic representation of the mechanism of action of CHK1/CHK2 inhibitor. In both normal and tumor cells, the recognition of damages on DNA by the DDR-sensors activates different cell cycle checkpoints. The central event of checkpoint activation is the inhibition of the phosphatases CDC25s which is necessary for the activation of the complexes CDK-cyclins. Both ATR/CHK1 and ATM/CHK2 pathways promote CDC25s inhibition (ubiquitin-dependent degradation) and, consequently, they arrest cell cycle in response to DNA damages. Tumor cells can activate these pathways in response to DNA damaging agents and survive. The treatment with a CHK1/CHK2 inhibitor avoids the degradation of the phosphatase CDC25s, inducing cell cycle progression even in the presence of DNA damages. For this reason, different CHK1/CHK2 inhibitors have been developed to enhance the DNA damaging from chemotherapeutic drugs by inhibiting the cell cycle checkpoint negative signals
Fig. 5
Fig. 5
Schematic representation of the mechanism of action of the WEE1 inhibitor. In both normal and tumor cells, the activation of WEE1 upon induction of DNA damage is not fully understood. WEE1 phosphorylates both CDK1/CDK2 to prevent the constitution of the complexes CDK/cyclins. Inhibition of WEE1 activity prevents the phosphorylation of CDKs and impairs the cell cycle checkpoint after DNA damage induction. This may lead to apoptosis upon treatment with DNA damaging chemotherapeutic agents
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