title: Defective K-Ras oncoproteins overcome impaired effector activation to initiate leukemia in vivo.
abstract: Reversing the aberrant biochemical output of oncogenic Ras proteins is one of the great challenges in cancer therapeutics; however, it is uncertain which Ras effectors are required for tumor initiation and maintenance. To address this question, we expressed oncogenic K-Ras(D12) proteins with "second site" amino acid substitutions that impair PI3 kinase/Akt or Raf/MEK/ERK activation in bone marrow cells and transplanted them into recipient mice. In spite of attenuated signaling properties, defective K-Ras oncoproteins initiated aggressive clonal T-lineage acute lymphoblastic leukemia (T-ALL). Murine T-ALLs expressing second site mutant proteins restored full oncogenic Ras activity through diverse mechanisms, which included acquiring novel somatic third site Kras(D12) mutations and silencing PTEN. T-ALL cell lines lacking PTEN had elevated levels of phosphorylated Akt, a gene expression pattern similar to human early T-cell precursor ALL, and were resistant to the potent and selective MEK inhibitor PD0325901. Our data, which demonstrate strong selective pressure to overcome the defective activation of PI3 kinase/Akt and Raf/MEK/ERK, implicate both Ras effector pathways as drivers of aberrant growth in T-ALL and further suggest that leukemia cells will deploy multiple mechanisms to develop resistance to targeted inhibitors in vivo.
authors: Department of Pediatrics and Division of Pediatric Hematology and Oncology, School of Medicine, University of California-San Francisco, CA, USA.
authors: Angell
authors: A
authors: Shieh
authors: Ashley F
authors: AF
authors: Ward
authors: Kegan L
authors: KL
authors: Donlan
authors: Emily R
authors: ER
authors: Harding-Theobald
authors: Jin
authors: J
authors: Xu
authors: Charles G
authors: CG
authors: Mullighan
authors: Chao
authors: C
authors: Zhang
authors: Shann-Ching
authors: SC
authors: Chen
authors: Xiaoping
authors: X
authors: Su
authors: James R
authors: JR
authors: Downing
authors: Gideon E
authors: GE
authors: Bollag
authors: Kevin M
authors: KM
authors: Shannon
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D019556:COS Cells; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D020125:Mutation, Missense; D015689:Oncogene Protein p21(ras) / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D048490:raf Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D048049:Extracellular Signal-Regulated MAP Kinases; D015689:Oncogene Protein p21(ras); D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D048490:raf Kinases; C487757:Pten protein, mouse
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