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Editorials
DNA damage on the DOCK in FLT3-ITD-driven acute myeloid leukemia
Ruchi Pandey and Reuben Kapur
Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, IN, USA E-mail: RUCHI PANDEY - pandeyru@iupui.edu or REUBEN KAPUR - rkapur@iupui.edu doi:10.3324/haematol.2019.231340
Induction of DNA damage by chemotherapeutics has been the mainstay of cancer therapy irrespective of the origin of the cancer. However, in acute myeloid leukemia (AML) responses to intensive chemotherapy differ greatly, with the success rate ranging very widely from 94% to 17% depending upon the karyotype of the patients.1 In particular, AML patients with normal cytoge- netics initially respond to DNA damaging agents but fre- quently relapse and have a 5-year survival rate of around 30%. The inferior survival in these patients correlates with the presence of internal tandem duplications (ITD) in FLT3, a cytokine receptor with tyrosine kinase activity, found in almost one-third of AML patients. Constitutively active FLT3-ITD contributes to increased proliferation and survival of myeloid progenitor cells. Although FLT3-ITD by itself is not considered a driver of AML, the presence of the mutation at both diagnosis and relapse highlights the importance of FLT3-ITD in resist- ance of leukemia-initiating cells to therapy. FLT3-ITD can activate all the major signaling pathways, such as Ras/ERK, JAK/STAT5 and PI3K/AKT but we still do not completely understand how these lead to resistance to chemotherapy and whether they create any vulnerabili- ties that could be exploited. FLT3-ITD activates the NADPH oxidase system through RAC1 to augment the production of reactive oxygen species (ROS) and a conse- quent adaptive response involving RAD51-mediated error prone repair and enhanced genomic instability.2 Interestingly, increased ROS production is not associated with the tyrosine kinase domain mutated FLT3, which incidentally is also not associated with poor prognosis. These suggest that increased DNA damage response (DDR) and genomic instability are important for the poor response to therapy in FLT3-ITD-positive (FLT3-ITD+) AML patients. In the current issue of Haematologica, Wu et al.3 provide evidence of involvement of a FLT3- ITD/DOCK2/ RAC1 self-sustaining positive feedback loop leading to upregulation of DDR proteins that con- tributes to chemotherapy resistance (Figure 1). They pro- vide evidence for the crucial role played by DOCK2 in mediating chemoresistance through regulating the RAC1/STAT5/DDR axis.3 Although expression of FLT3- ITD has been associated with resistance to chemothera- py and it has long been known that inhibition of signaling by kinase inhibitors can sensitize leukemic cells,4 this had not been extensively explored or utilized in the clinic. Only recently, is it becoming evident that midostaurin (PKC412), a multi-kinase inhibitor, is much more effec- tive at inducing sustained remissions when used in com- bination with chemotherapy than when used as single- agent therapy.5 The results presented by Wu et al.3 further emphasize the role of chemo-sensitization through inhi- bition of signaling by mutant FLT3 and provide a way for-
ward for improving the clinical outcome in FLT3-ITD+ AML patients.
Activation of RAC1 by FLT3-ITD has been recognized as the major contributor to enhanced DDR but the ubiq- uitous expression of RAC1 and its involvement in multi- ple processes makes targeting RAC1 specifically in leukemic cells a challenge.6 DOCK2, an atypical guanine nucleotide exchange factor, has previously been identi- fied as an intermediate between FLT3-ITD and STAT5.7 DOCK2 has much more restricted expression, acts upstream of RAC1 and is required for upregulation of the DDR pathway. Combining loss of DOCK2 with cytara- bine produced a similar increase in cytotoxicity as that observed with inhibiting the kinase function of FLT3-ITD (Figure 1).3 The alternative pathways from FLT3-ITD, such as FAK/TIAM1 and DOCK2, culminating in activa- tion of RAC1 and subsequent nuclear translocation of STAT5 provide additional points of vulnerability that could be therapeutically exploited to overcome acquired drug resistance in response to FLT3-specific small mole- cule inhibitors.7,8 DOCK2 mutations leading to activation of RAC1 have also been identified in gastrointestinal and prostate cancers. It remains to be seen if similar deregula- tion of the DDR pathway is involved in carcinogenesis across different types of cancers.
The synthetic lethality observed with DOCK2 inhibi- tion upon treatment with cytarabine could be attributed to downregulation of FLT3-ITD and the DDR pathway.3 However, Wu et al.3 did not observe a similar synergism when inhibitors of individual components of the DDR such as CHK1 (MK8776) or WEE1 (MK1775) were used in combination with cytarabine. As expected, the concur- rent use of inhibitors of CHK1 and WEE1 with DOCK2 inhibition showed marginal improvements since DOCK2 knockdown significantly reduces both FLT3-ITD and these DDR pathway proteins.3 Functional redundancy between DDR proteins may account for lack of syner- gism between MK8776 or MK1775 and cytarabine.3 Although targeting DOCK2 appears to be more benefi- cial; the clinical translation of co-targeting DOCK2 is lim- ited due to non-availability of potent and specific inhibitors. Currently two small molecule inhibitors of DOCK2 are available: the chemically synthesized 4-[3’- (2’’-chlorophenyl)-2’-propen-1’-ylidene]-1-phenyl-3,5- pyrazolidinedione (CPYPP)9 and a naturally occurring cholesterol sulfate.10 The effects of these inhibitors of DOCK2 have been evaluated in the immune system and they have been found to block RAC1 activation but a comprehensive evaluation in AML models has not been carried out. The significance of targeting DOCK2 in sen- sitizing FLT3-ITD+ AML cells to chemotherapy demon- strated by Wu et al.3 may provide the impetus for devel- opment of therapeutic strategies to target DOCK2 in
haematologica | 2019; 104(12)