Acid Ceramidase Inhibitor LCL-805 Antagonizes Akt Signaling and Promotes Iron-Dependent Cell Death in Acute Myeloid Leukemia

Ung, J.; Tan, S.-F.; Fox, T. E.; Shaw, J. J.; Taori, M.; Horton, B. J.; Golla, U.; Sharma, A.; Szulc, Z. M.; Wang, H.-G.; Chalfant, C. E.; Cabot, M. C.; Claxton, D. F.; Loughran, T. P.; Feith, D. J.

doi:10.1101/2023.10.21.563437

bioRxiv · 10.1101/2023.10.21.563437

Acid Ceramidase Inhibitor LCL-805 Antagonizes Akt Signaling and Promotes Iron-Dependent Cell Death in Acute Myeloid Leukemia

Ung, J.·Tan, S.-F.·Fox, T. E.·Shaw, J. J.·Taori, M.·Horton, B. J.·Golla, U.·Sharma, A.·Szulc, Z. M.·Wang, H.-G.·Chalfant, C. E.·Cabot, M. C.·Claxton, D. F.·Loughran, T. P.·Feith, D. J.

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Abstract

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy requiring urgent treatment advancements. Ceramide is a cell death-promoting signaling lipid that plays a central role in therapy-induced cell death. Acid ceramidase (AC), a ceramide-depleting enzyme, is overexpressed in AML and promotes leukemic survival and drug resistance. The ceramidase inhibitor B-13 and next-generation lysosomal-localizing derivatives termed dimethylglycine (DMG)-B-13 prodrugs have been developed but remain untested in AML. Here, we report the in vitro anti-leukemic efficacy and mechanism of DMG-B-13 prodrug, LCL-805, across AML cell lines and primary patient samples. LCL-805 inhibited AC enzymatic activity, increased total ceramides, and reduced sphingosine levels. A median EC50 value of 11.7 M was achieved for LCL-805 in cell viability assays across 32 human AML cell lines. As a single agent tested across a panel of 71 primary AML patient samples, a median EC50 value of 15.8 M was achieved. Exogenous ceramide supplementation with C6-ceramide nanoliposomes, which is entering phase I/II clinical trial for relapsed/refractory AML, significantly enhanced LCL-805 killing. Mechanistically, LCL-805 antagonized Akt signaling and led to iron-dependent cell death distinct from canonical ferroptosis. These findings elucidated key factors involved in LCL-805 cytotoxicity and demonstrated the potency of combining AC inhibition with exogenous ceramide.

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Ung, J., Tan, S.-F., Fox, T. E., Shaw, J. J., Taori, M., Horton, B. J., Golla, U., Sharma, A., Szulc, Z. M., Wang, H.-G., Chalfant, C. E., Cabot, M. C., Claxton, D. F., Loughran, T. P., Feith, D. J.. 2023-10-23. Acid Ceramidase Inhibitor LCL-805 Antagonizes Akt Signaling and Promotes Iron-Dependent Cell Death in Acute Myeloid Leukemia. https://doi.org/10.1101/2023.10.21.563437

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