RIPK1 inhibition enhances the therapeutic efficacy of chidamide in FLT3-ITD positive AML, both in vitro and in vivo

Abstract

Acute myeloid leukemia (AML) with FLT3-ITD mutation accounts for a large proportion of relapsed/refractory AML with poor prognosis. RIPK1 is a known key regulator of necroptosis and RIPK1 inhibition shows anti-AML effects in vitro. Chidamide is a histone deacetylase inhibitor (HDACi) with proven ability to induce apoptosis in FLT3-ITD positive AML cells. In the present study, we evaluated the effects of the combination of 22b, a novel RIPK1 inhibitor, and chidamide on proliferation and apoptosis in FLT3-ITD positive AML cell lines and primary cells. The results showed that 22b could significantly enhance the anti-leukemia effect of low-dose chidamide both on cell lines and primary cells. In a subcutaneous xenograft AML model, the combination of 22b and chidamide exhibited obviously elevated anti-tumor activity. In conclusion, our results support that the combination of RIPK1 inhibitor 22b and chidamide may be a novel therapeutic avenue for FLT3-ITD positive AML patients.

Keywords:

• Receptor-interacting protein kinase-1
• acute myeloid leukemia
• FLT3-ITD
• chidamide
• necroptosis

Acknowledgements

The authors thank Shenzhen Chipscreen Biosciences Co., Ltd. for the kind gift of chidamide.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by grants from the National Natural Science Foundation of China [No. 81930125], Incubation Program for Clinical Trials [No. 19HXFH030], 1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University [No. ZYJC21007], Translational Research Grant of NCRCH [No. 2021WWB03] and Natural Science Foundation of Hunan Province [No. 2021JJ40501].