In vivo validation of the palmitoylation cycle as a therapeutic target in NRAS-mutant cancer

Decker, M.; Huang, B. J.; Ware, T.; Boone, C.; Tang, M.; Ybarra, J.; Ballapuram, A. C.; Taran, K. A.; Chen, P.-Y.; Amendariz, M.; Leung, C. J.; Harris, M.; Tjoa, K.; Hongo, H.; Abelson, S.; Rivera, J.; Ngo, N.; Herbst, D. M.; Suciu, R. M.; Guijas, C.; Sedighi, K.; Andalis, T.; Roche, E.; Xie, B.; Liu, Y.; Smith, C. C.; Stieglitz, E.; Niphakis, M. J.; Cravatt, B.; Shannon, K.

doi:10.1101/2025.03.20.644389

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bioRxiv · 10.1101/2025.03.20.644389

In vivo validation of the palmitoylation cycle as a therapeutic target in NRAS-mutant cancer

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Abstract

Ras proteins are functionally dependent on one or more lipid modifications.1,2 The dynamic palmitoylation of N-Ras by DHHC palmitoyl acyltransferases and depalmitoylation by ABHD17 serine hydrolases is essential for the growth of NRAS-mutant acute myeloid leukemia (AML) cells.3-6 Here we show that ABD778, an in vivo-active ABHD17 inhibitor, selectively reduces the growth of NRAS-mutant AML and melanoma cell lines and is synergistic with the MEK inhibitor PD0325901 (PD901; mirdametinib). Mechanistically, ABD778 and PD901 induce deep and durable suppression of mitogen activated protein kinase (MAPK) pathway activation. Co-treatment extended the survival of mice transplanted with NrasG12D AMLs, which acquired by-pass mutations at relapse that conferred drug resistance and restored MAPK activation. ABD778 augmented the anti-leukemia activity of PI3 kinase, pan-Ras tri-complex, and FLT3 inhibitors, and restored gilteritinib sensitivity in a patient-derived xenograft model of FLT3 inhibitor resistance. These studies validate the palmitoylation cycle as a therapeutic target in NRAS-mutant cancers.

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Decker, M., Huang, B. J., Ware, T., Boone, C., Tang, M., Ybarra, J., Ballapuram, A. C., Taran, K. A., Chen, P.-Y., Amendariz, M., Leung, C. J., Harris, M., Tjoa, K., Hongo, H., Abelson, S., Rivera, J., Ngo, N., Herbst, D. M., Suciu, R. M., Guijas, C., Sedighi, K., Andalis, T., Roche, E., Xie, B., Liu, Y., Smith, C. C., Stieglitz, E., Niphakis, M. J., Cravatt, B., Shannon, K.. 2025-03-21. In vivo validation of the palmitoylation cycle as a therapeutic target in NRAS-mutant cancer. https://doi.org/10.1101/2025.03.20.644389

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