title: Isoprenylcysteine carboxylmethyltransferase is critical for malignant transformation and tumor maintenance by all RAS isoforms.
abstract: Despite extensive effort, there has been limited progress in the development of direct RAS inhibitors. Targeting isoprenylcysteine carboxylmethyltransferase (ICMT), a unique enzyme of RAS post-translational modification, represents a promising strategy to inhibit RAS function. However, there lacks direct genetic evidence on the role of ICMT in RAS-driven human cancer initiation and maintenance. Using CRISPR/Cas9 genome editing, we have created Icmt loss-of-function isogenic cell lines for both RAS-transformed human mammary epithelial cells (HME1) and human cancer cell lines MiaPaca-2 and MDA-MB-231 containing naturally occurring mutant KRAS. In both in vitro and in vivo tumorigenesis studies, Icmt loss-of-function abolishes the tumor initiation ability of all major isoforms of mutant RAS in HME1 cells, and the tumor maintenance capacity of MiaPaca-2 and MDA-MB-231 cells, establishing the critical role of ICMT in RAS-driven cancers.
authors.affiliation: Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.
authors.forename: H Y
authors.initials: HY
authors.lastname: Lau
authors.affiliation: Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.
authors.forename: J
authors.initials: J
authors.lastname: Tang
authors.affiliation: Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.
authors.forename: P J
authors.initials: PJ
authors.lastname: Casey
authors.affiliation: Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.|Department of Biochemistry, National University of Singapore, Singapore.
authors.forename: M
authors.initials: M
authors.lastname: Wang
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D006801:Humans; D016513:Mice, SCID; D020125:Mutation, Missense; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D011496:Protein Methyltransferases / Q000502:physiology*; D013629:Tamoxifen / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D018631:ras Proteins / Q000235:genetics* / Q000378:metabolism
chemical_list: D018931:Antineoplastic Agents, Hormonal; D020033:Protein Isoforms; D013629:Tamoxifen; D011496:Protein Methyltransferases; C056501:protein-S-isoprenylcysteine O-methyltransferase; D018631:ras Proteins