In vivo validation of the palmitoylation cycle as a therapeutic target in NRAS-mutant cancer.
| Title: | In vivo validation of the palmitoylation cycle as a therapeutic target in NRAS-mutant cancer. |
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| Authors: | Decker M; Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.; Huang BJ; Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.; Ware T; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.; Boone C; Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.; Tang M; Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.; Ybarra J; Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.; Ballapuram AC; Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.; Taran KA; Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.; Chen PY; Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.; Amendáriz M; Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.; Leung CJ; Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.; Harris M; Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.; Tjoa K; Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.; Hongo H; Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.; Abelson S; Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.; Rivera J; Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.; Ngo N; Lundbeck La Jolla Research Center, Inc., San Diego, CA, USA.; Herbst DM; Lundbeck La Jolla Research Center, Inc., San Diego, CA, USA.; Suciu RM; Lundbeck La Jolla Research Center, Inc., San Diego, CA, USA.; Guijas C; Lundbeck La Jolla Research Center, Inc., San Diego, CA, USA.; Sedighi K; Lundbeck La Jolla Research Center, Inc., San Diego, CA, USA.; Andalis T; Lundbeck La Jolla Research Center, Inc., San Diego, CA, USA.; Roche E; Lundbeck La Jolla Research Center, Inc., San Diego, CA, USA.; Xie B; Lundbeck La Jolla Research Center, Inc., San Diego, CA, USA.; Liu Y; Center for Center for Medical Genomics, Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.; Smith CC; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.; Stieglitz E; Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.; Niphakis MJ; Lundbeck La Jolla Research Center, Inc., San Diego, CA, USA.; Cravatt BF; Department of Chemistry, The Scripps Research Institute, La Jolla, CA, USA.; Shannon K; Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA. |
| Source: | BioRxiv : the preprint server for biology [bioRxiv] 2025 Mar 21. Date of Electronic Publication: 2025 Mar 21. |
| Publication Type: | Journal Article; Preprint |
| Language: | English |
| Journal Info: | Country of Publication: United States NLM ID: 101680187 Publication Model: Electronic Cited Medium: Internet ISSN: 2692-8205 (Electronic) Linking ISSN: 26928205 NLM ISO Abbreviation: bioRxiv Subsets: PubMed not MEDLINE |
| Abstract: | Normal and oncogenic Ras proteins are functionally dependent on one or more lipid modifications1,2. Whereas K-Ras4b farnesylation is sufficient for stable association with the plasma membrane, farnesylated H-Ras, K-Ras4a, and N-Ras traffic to the Golgi where they must undergo palmitoylation before regulated translocation to cell membranes. N-Ras palmitoylation by the DHHC family of palmitoyl acyl transferases (PATs) and depalmitoylation by ABHD17 serine hydrolases is a dynamic process that is essential for the growth of acute myeloid leukemias (AMLs) harboring oncogenic NRAS mutations3-6. Here, we have tested whether co-targeting ABHD17 enzymes and Ras signal output would cooperatively inhibit the proliferation and survival of NRAS-mutant AMLs while sparing normal tissues that retain K-Ras4b function. We show that ABD778, a potent and selective ABHD17 inhibitor with in vivo activity, selectively reduces the growth of NRAS-mutant AML cells in vitro and is synergistic with the allosteric MEK inhibitor PD0325901 (PD901)7,8. Similarly, ABD778 and PD901 significantly extended the survival of recipient mice transplanted with three independent primary mouse AMLs harboring an oncogenic Nras G12D, the K/N-Ras9, the K/N-RasG12C inhibitor sotorasib10, and the FLT3 inhibitor gilteritinib11. Co-treatment with ABD778 and gilteritinib restored drug sensitivity in a patient-derived xenograft model of adaptive resistance to FLT3 inhibition. These data validate the palmitoylation cycle as a promising therapeutic target in AML and support exploring it in other NRAS-mutant cancers. |
| Competing Interests: | Competing interests Nhi Ngo, Dylan M. Herbst, Radu M. Suciu, Carlos Guijas, Kimia Sedighi, Taylor Andalis, Elysia Roche, Boer Xie, and Micah J. Niphakis are full-time employees of Lundbeck. The authors declare no other competing interests. |
| Grant Information: | U54 CA196519 United States CA NCI NIH HHS; K08 CA256489 United States CA NCI NIH HHS; R37 CA266550 United States CA NCI NIH HHS; R01 CA193994 United States CA NCI NIH HHS; R35 CA231991 United States CA NCI NIH HHS; T32 CA128583 United States CA NCI NIH HHS |
| Entry Date(s): | Date Created: 20250401 Latest Revision: 20250424 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC11957127 |
| DOI: | 10.1101/2025.03.20.644389 |
| PMID: | 40166265 |
| Database: | MEDLINE |
Journal Article; Preprint