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M. Wu et al.
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Figure 5. DOCK2 knockdown in transplanted MV4;11 cells enhanced the treatment benefit of ara-C in NSG mice, both alone and in combination with MK8776. (A) Survival of immunodeficient NSG mice transplanted with MV4;11 cells (0.6 x 106 cells) after daily intraperitoneal (i.p.) injections of vehicle, ara-C (50 mg/kg), MK8776 (10 mg/kg), MK1775 (15 mg/kg), ara-C+MK8776, or ara-C+MK1775 for 3 consecutive days. When combined with ara-C, MK8776 and MK1775 were inject- ed 30 min after the ara-C injection. (B) Bone marrow blast percentage was measured 7 days after the start of treatment. The combined treatment with ara-C and MK8776 resulted in significantly reduced bone marrow blast percentage in NSG mice transplanted with DOCK2 KD MV4;11 cells, compared with mice treated with either single agent. *P<0.05; **P<0.01. C: mice transplanted with MV4;11 cells expressing control short hairpin (sh)RNA; KD: mice transplanted with MV4;11 cells expressing shRNA against DOCK2.
when DOCK2 was knocked-down in FLT3-ITD leukemic cells. Thus, DOCK2/Rac1 and FLT3-ITD appear to form a positive feedback loop, and cooperate to modulate cellular DDR activities (Figure 6).
Rac1 itself is a challenging therapeutic target due to its widespread expression and diverse cellular functions.49 As a tissue-specific Rac1 effector, DOCK2 may prove to be a
more feasible target in that its inhibition allows for hematopoietic-specific Rac1 inhibition. Although DOCK2 inhibitors are not currently widely available, small molec- ular inhibitors of DOCK2 have been reported.50 Moreover, screening of pre-existing drug libraries may be warranted to uncover potential novel DOCK2 inhibitors.
Various regulators of DDR have also been investigated
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haematologica | 2019; 104(12)