Targeting CERT sensitizes AML Cells to FLT3 Inhibitors through activating GRP78-ATF6-CHOP Axis

Ceramide Transfer Protein (CERT) determines the ratio of ceramide and Sphingomyelin in cells. Targeting CERT sensitizes solid cancer cells to chemotherapy. However, the role of CERT in AML remains elusive. Knockdown CERT or its inhibitor HPA-12 inhibited growth and promoted apoptosis in AML cells carrying FLT3-ITD mutation. HPA-12 alone or with the FLT3 inhibitor Crenolanib synergistically inhibited proliferation and triggered apoptosis in FLT3-ITD mutated AML cells in vitro and in vivo. Interestingly, co-treatment of HPA-12 and Crenolanib is effective in FLT3-ITD+ and FLT3-TKD+ AML patients. The synergistic effects were mediated by the endoplasmic reticulum (ER) stress-GRP78/ATF6/CHOP axis and mitophagy. Our data suggest a possible strategy to enhance the efficacy of FLT3 inhibitors in AML. both including DMSO, 48 h HPA-12 and Creno at the indicated concentrations alone or in combination treatment groups