title: Cell-Specific Computational Modeling of the PIM Pathway in Acute Myeloid Leukemia.
abstract: Personalized therapy is a major goal of modern oncology, as patient responses vary greatly even within a histologically defined cancer subtype. This is especially true in acute myeloid leukemia (AML), which exhibits striking heterogeneity in molecular segmentation. When calibrated to cell-specific data, executable network models can reveal subtle differences in signaling that help explain differences in drug response. Furthermore, they can suggest drug combinations to increase efficacy and combat acquired resistance. Here, we experimentally tested dynamic proteomic changes and phenotypic responses in diverse AML cell lines treated with pan-PIM kinase inhibitor and fms-related tyrosine kinase 3 (FLT3) inhibitor as single agents and in combination. We constructed cell-specific executable models of the signaling axis, connecting genetic aberrations inFLT3, tyrosine kinase 2 (TYK2), platelet-derived growth factor receptor alpha (PDGFRA), and fibroblast growth factor receptor 1 (FGFR1) to cell proliferation and apoptosis via thePIMandPI3Kkinases. The models capture key differences in signaling that later enabled them to accurately predict the unique proteomic changes and phenotypic responses of each cell line. Furthermore, using cell-specific models, we tailored combination therapies to individual cell lines and successfully validated their efficacy experimentally. Specifically, we showed that cells mildly responsive to PIM inhibition exhibited increased sensitivity in combination with PIK3CA inhibition. We also used the model to infer the origin of PIM resistance engineered through prolonged drug treatment of MOLM16 cell lines and successfully validated experimentally our prediction that this resistance can be overcome with AKT1/2 inhibition.Cancer Res; 77(4); 827-38. ©2016 AACR.
authors.affiliation: Department of Computer Science, Tel-Aviv University, Tel-Aviv, Israel.|Microsoft Research, Cambridge, UK.
authors.forename: Dana
authors.initials: D
authors.lastname: Silverbush
authors.affiliation: AstraZeneca Oncology IMED, Waltham, Massachusetts.
authors.forename: Shaun
authors.initials: S
authors.lastname: Grosskurth
authors.affiliation: AstraZeneca Oncology IMED, Cambridge, UK.
authors.forename: Dennis
authors.initials: D
authors.lastname: Wang
authors.affiliation: AstraZeneca Oncology IMED, Waltham, Massachusetts.
authors.forename: Francoise
authors.initials: F
authors.lastname: Powell
authors.affiliation: Department of Haematology, Cambridge Institute for Medical Research and Wellcome Trust and MRC Stem Cell Institute, University of Cambridge, UK.
authors.forename: Berthold
authors.initials: B
authors.lastname: Gottgens
authors.affiliation: AstraZeneca Oncology IMED, Waltham, Massachusetts. jf416@cam.ac.uk jonathan.dry@astrazeneca.com.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Dry
authors.affiliation: Microsoft Research, Cambridge, UK. jf416@cam.ac.uk jonathan.dry@astrazeneca.com.|Department of Biochemistry, University of Cambridge, Cambridge, UK.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Fisher
mesh_terms: D001713:Biphenyl Compounds / Q000627:therapeutic use; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases; D003198:Computer Simulation; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000503:physiopathology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D053778:Thiazolidines / Q000627:therapeutic use; D051941:fms-Like Tyrosine Kinase 3 / Q000037:antagonists & inhibitors*
chemical_list: C587575:AZD1208; D001713:Biphenyl Compounds; D000081082:Phosphoinositide-3 Kinase Inhibitors; D053778:Thiazolidines; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C497970:FLT3 protein, human; D051941:fms-Like Tyrosine Kinase 3; D051573:Proto-Oncogene Proteins c-pim-1; C406031:proto-oncogene proteins pim; D020929:Mitogen-Activated Protein Kinase Kinases