title: Inhibition of isoprenylcysteine carboxylmethyltransferase augments BCR-ABL1 tyrosine kinase inhibition-induced apoptosis in chronic myeloid leukemia.
abstract: Despite the success of BCR-ABL1 tyrosine kinase inhibitors in patients with chronic myeloid leukemia (CML), resistance to tyrosine kinase inhibitors remains a therapeutic challenge. One strategy used to overcome resistance is combination of existing BCR-ABL1 tyrosine kinase inhibitors with agents that target alternative pathways. We report that inhibition of isoprenylcysteine carboxylmethyltransferase (Icmt), a key enzyme in the protein prenylation pathway, with the selective inhibitor cysmethynil enhances the effect of BCR-ABL1 tyrosine kinase inhibitors in killing CML cells. Cysmethynil augments tyrosine kinase inhibitor-induced apoptosis in both BCR-ABL1 wild type and BCR-ABL1 kinase domain mutant-expressing cell lines. Importantly, the enhanced apoptosis observed with the combination of cysmethynil and imatinib is significant only in primary CML CD34+ progenitor cells, not normal cord blood progenitor cells. The combination was also selective in inhibiting colony formation in CML CD34+ cells. The enhanced apoptosis appears to be due to combination of immediate and persistent inhibition of MAPK signaling. Consistent with in vitro studies, cysmethynil and imatinib, in combination, enhance the in vivo effects of either drug used alone. We found that simultaneous inhibition of BCR-ABL1 and Icmt may represent a potential therapeutic strategy for CML.
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore.
authors.forename: Wen Tian
authors.initials: WT
authors.lastname: Sun
authors.affiliation: Department of Haematology, Singapore General Hospital, Singapore.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiang
authors.affiliation: Department of Haematology, Singapore General Hospital, Singapore.
authors.forename: Bee Ling
authors.initials: BL
authors.lastname: Ng
authors.affiliation: Department of Haematology, Singapore General Hospital, Singapore.
authors.forename: Kartini
authors.initials: K
authors.lastname: Asari
authors.affiliation: Office of Research, Duke-NUS Medical School, Singapore.
authors.forename: Ralph M
authors.initials: RM
authors.lastname: Bunte
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Casey
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore. Electronic address: mei.wang@duke-nus.edu.sg.
authors.forename: Mei
authors.initials: M
authors.lastname: Wang
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, Singapore; Department of Haematology, Singapore General Hospital, Singapore. Electronic address: charles.chuah.t.h@sgh.com.sg.
authors.forename: Charles
authors.initials: C
authors.lastname: Chuah
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D007211:Indoles / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D014411:Neoplastic Stem Cells / Q000201:enzymology / Q000473:pathology; D011496:Protein Methyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: C581634:BCR-ABL1 fusion protein, human; D007211:Indoles; C530692:cysmethynil; D000068877:Imatinib Mesylate; D011496:Protein Methyltransferases; D016044:Fusion Proteins, bcr-abl