Abstract
The success of all-trans retinoic acid (ATRA) in differentiation therapy for patients with acute promyelocytic leukemia (APL) highly encourages researches to apply this therapy to other types of acute myeloid leukemia (AML). However, AML, with the exception of APL, fails to respond to differentiation therapy. Therefore, research strategies to further sensitize cells to retinoids and to extend the range of AMLs that respond to retinoids beyond APLs are urgently needed. In this study, we showed that TAK165, a HER2 inhibitor, exhibited a strong synergy with ATRA to promote AML cell differentiation. We observed that TAK165 sensitized the AML cells to ATRA-induced cell growth inhibition, G0/G1 phase arrest, CD11b expression, mature morphologic changes, NBT reduction and myeloid regulator expression. Unexpectedly, HER2 pathway might not be essential for TAK165-enhanced differentiation when combined with ATRA, while the enhanced differentiation was dependent on the activation of the RARα/STAT1 axis. Furthermore, the MEK/ERK cascade regulated the activation of STAT1. Taken together, our study is the first to evaluate the synergy of TAK165 and ATRA in AML cell differentiation and to assess new opportunities for the combination of TAK165 and ATRA as a promising approach for future differentiation therapy.
Highlights
The success of all-trans retinoic acid (ATRA) in differentiation therapy for patients with acute promyelocytic leukemia (APL) highly encourages researches to apply this therapy to other types of acute myeloid leukemia (AML)
We found that the biological function of the combination of TAK165 and ATRA in inducing cell differentiation is driven by the activation of the RARα /STAT1 axis resulting from MEK/ERK phosphorylation instead of Human epidermal growth factor receptor 2 (HER2) inhibition
Because TAK165 is a specific HER2 inhibitor, which is reported to decrease cell proliferation and inhibit the G1/S transition in leukemia cells[28], we intended to evaluate whether TAK165 enhances the effect of ATRA by inhibiting HER2
Summary
The success of all-trans retinoic acid (ATRA) in differentiation therapy for patients with acute promyelocytic leukemia (APL) highly encourages researches to apply this therapy to other types of acute myeloid leukemia (AML). Our study is the first to evaluate the synergy of TAK165 and ATRA in AML cell differentiation and to assess new opportunities for the combination of TAK165 and ATRA as a promising approach for future differentiation therapy. The use of ATRA as a single agent is not approved for the clinical management of leukemia with the exception of APLs. a new differentiation therapy that improves the effectiveness of ATRA and extends the range of myeloid malignancies that respond to retinoids beyond APLs is urgently needed. This study evaluated the capacity of TAK165 to synergize with ATRA in AML cells and induce differentiation, and suggests that this combination therapy is a promising approach as a future differentiation therapy
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