Page 13 - Haematologica May 2020

Editorials
Figure 1. Chronic myeloid leukemia (CML) stem cells are resistant to tyrosine kinase inhibitors (TKI) due to multiple factors, including increased drug efflux.
Combined treatment with a TKI and an inhibitor of MDM2 (e.g. OS-5272) leads to hyper-activation of TP53 (A). The latter event results in upregulation of multiple pro-apoptotic effectors including NOXA and PUMA, which trigger LSC apoptosis. This phenomenon may be enhanced by NOXA-mediated degradation of the anti-apop- totic protein MCL-1. Alternatively, disabling of the anti-apoptotic protein BCL-2 (B) e.g. by ABT-199 (Venetoclax) may analogously lower the threshold for TKI-induced cell death in the CML LSC subpopulation. Eradication of such stem cells by simultaneous targeting of oncogenic (BCR/ABL) and orthogonal (TP53) pathways may delay or prevent re-emergence of disease.
While the results of the Carter et al. study support the notion that an agent such as OS-5272 may potentiate the activity of a TKI like IM, they also lay a foundation for the development of a wealth of additional strategies capable of targeting CML LSC. For example, apart from the possibili- ty of employing other MDM2 inhibitors, it would be of interest to assess interactions involving other agents that have been used to target BCR/ABL-expressing cells. These would include newer generation TKI such as the multi- kinase inhibitor ponatinib, which is active against BCR- ABL+ cells resistant to IM through the T315 mutation.11 An alternative candidate for combination with MDM2 inhibitors would be omacetaxine, a protein synthesis inhibitor which down-regulates BCR/ABL among other proteins, and which has shown significant activity against IM-resistant CML.12 Based upon the present results, there would seem to be a reasonable chance that MDM2 antag- onist regimens incorporating these agents would also tar- get LSC. In addition, as noted by the authors, the BCL-2 antagonist ABT-199 is known to target LSC,13 and has also been shown to increase TKI activity against primitive LSC.3 If tolerable, adding ABT-199 to the MDM2 antago- nist/IM regimen may prove to be particularly effective in eliminating the LSC population. Aside from this approach, recent attention has focused on the development of MCL- 1 antagonists as anti-leukemic agents,14 in part due to evi- dence that MCL-1 is required by CML LSC for survival.15
In view of these considerations, the notion of using a clin- ically relevant MCL-1 antagonist to further enhance the activity of an MDM2 antagonist/TKI regimen against CML LSC appears worthy of investigation.
In summary, the present report argues that, in CML, LSC exhibit a potentially selective activation of TP53 which can be exploited through the use of MDM2 antag- onists, and that this phenomenon can act in concert with TKI inhibitors to trigger cell death in this difficult to erad- icate leukemic cell subpopulation. Whereas in the past, attention focused on the identification of novel TKI able to overcome mutational forms of resistance, more current approaches are based on the development of strategies designed to disrupt orthogonal, non-oncogenic pathways,16 including those related to TP53. However, whether such dual-targeting strategies will prove capable of eliminating primitive stem cells has not yet been defin- itively established. The results presented here strongly support the concept of simultaneous targeting of onco- genic drivers (e.g. BCR/ABL) and orthogonal pathways (e.g. TP53) to eradicate these cells, at least in the case of CML. Given the large array of targeted agents that are now clinically available, including MDM2 inhibitors and modulators of the apoptotic response, LSC-directed ther- apy in CML and related disorders is currently underway. Determining whether such novel strategies will live up to their pre-clinical promise is only a matter of time.
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