title: Preclinical efficacy of MEK inhibition in Nras-mutant AML.
abstract: Oncogenic NRAS mutations are highly prevalent in acute myeloid leukemia (AML). Genetic analysis supports the hypothesis that NRAS mutations cooperate with antecedent molecular lesions in leukemogenesis, but have limited independent prognostic significance. Using short hairpin RNA-mediated knockdown in human cell lines and primary mouse leukemias, we show that AML cells with NRAS/Nras mutations are dependent on continued oncogene expression in vitro and in vivo. Using the Mx1-Cre transgene to inactivate a conditional mutant Nras allele, we analyzed hematopoiesis and hematopoietic stem and progenitor cells (HSPCs) under normal and stressed conditions and found that HSPCs lacking Nras expression are functionally equivalent to normal HSPCs in the adult mouse. Treating recipient mice transplanted with primary Nras(G12D) AMLs with 2 potent allosteric mitogen-activated protein kinase kinase (MEK) inhibitors (PD0325901 or trametinib/GlaxoSmithKline 1120212) significantly prolonged survival and reduced proliferation but did not induce apoptosis, promote differentiation, or drive clonal evolution. The phosphatidylinositol 3-kinase inhibitor GDC-0941 was ineffective as a single agent and did not augment the activity of PD0325901. All mice ultimately succumbed to progressive leukemia. Together, these data validate oncogenic N-Ras signaling as a therapeutic target in AML and support testing combination regimens that include MEK inhibitors.
authors.affiliation: Divisions of Hematology/Oncology, Department of Medicine and.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Burgess
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, CA;
authors.forename: Eugene
authors.initials: E
authors.lastname: Hwang
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, CA;
authors.forename: Ari J
authors.initials: AJ
authors.lastname: Firestone
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, CA;
authors.forename: Tannie
authors.initials: T
authors.lastname: Huang
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, CA;
authors.forename: Jin
authors.initials: J
authors.lastname: Xu
authors.affiliation: Research Institute of Molecular Pathology, Vienna, Austria;
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuber
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI;
authors.forename: Natacha
authors.initials: N
authors.lastname: Bohin
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI;
authors.forename: Tiffany
authors.initials: T
authors.lastname: Wen
authors.affiliation: Laboratory Medicine, University of California, San Francisco, San Francisco, CA;
authors.forename: Scott C
authors.initials: SC
authors.lastname: Kogan
authors.affiliation: Molecular Pathology Unit and Center for Cancer Research, Massachusetts General Hospital, Charlestown, MA;
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Haigis
authors.affiliation: Department of Translational Oncology, Genentech Inc., South San Francisco, CA;
authors.forename: Deepak
authors.initials: D
authors.lastname: Sampath
authors.affiliation: Howard Hughes Medical Institute; Memorial Sloan Kettering Cancer Center, New York, NY; and.
authors.forename: Scott
authors.initials: S
authors.lastname: Lowe
authors.affiliation: Department of Pediatrics, University of California San Francisco, San Francisco, CA; Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Shannon
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, University of Michigan, Ann Arbor, MI;
authors.forename: Qing
authors.initials: Q
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D011905:Genes, ras; D006412:Hematopoietic Stem Cells / Q000166:cytology; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000737:chemistry; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology; D019076:Transgenes
chemical_list: D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D020930:MAP Kinase Kinase Kinases; D020559:Monomeric GTP-Binding Proteins; C586503:Nras protein, mouse