{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,26]],"date-time":"2026-08-26T06:27:10Z","timestamp":1787725630265,"version":"build-2784847793"},"posted":{"date-parts":[[2025,3,21]]},"group-title":"Cancer Biology","reference-count":82,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,3,21]],"date-time":"2025-03-21T00:00:00Z","timestamp":1742515200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,7,19]]},"abstract":"<jats:title>SUMMARY<\/jats:title>\n                <jats:p>\n                  Ras proteins are functionally dependent on one or more lipid modifications.\n                  <jats:sup>1,2<\/jats:sup>\n                  The dynamic palmitoylation of N-Ras by DHHC palmitoyl acyltransferases and depalmitoylation by ABHD17 serine hydrolases is essential for the growth of\n                  <jats:italic>NRAS<\/jats:italic>\n                  -mutant acute myeloid leukemia (AML) cells.\n                  <jats:sup>3\u20136<\/jats:sup>\n                  Here we show that ABD778, an\n                  <jats:italic>in vivo<\/jats:italic>\n                  -active ABHD17 inhibitor, selectively reduces the growth of\n                  <jats:italic>NRAS<\/jats:italic>\n                  -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\n                  <jats:italic>\n                    Nras\n                    <jats:sup>G12D<\/jats:sup>\n                  <\/jats:italic>\n                  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\n                  <jats:italic>NRAS<\/jats:italic>\n                  -mutant cancers.\n                <\/jats:p>","DOI":"10.1101\/2025.03.20.644389","type":"posted-content","created":{"date-parts":[[2025,3,23]],"date-time":"2025-03-23T23:42:50Z","timestamp":1742773370000},"source":"Crossref","is-referenced-by-count":3,"title":["<i>In Vivo<\/i>\n                  Efficacy of ABHD17 Inhibition Validates the Palmitoylation Cycle as a Therapeutic Target in\n                  <i>NRAS<\/i>\n                  -Mutant Cancer"],"prefix":"10.64898","author":[{"given":"Matthew","family":"Decker","sequence":"first","affiliation":[{"name":"Department of Pediatrics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin J.","family":"Huang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics"},{"name":"Helen Diller Family Comprehensive Cancer Center, University of California, San 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