title: Leukemias induced by altered TRK-signaling are sensitive to mTOR inhibitors in preclinical models.
abstract: Rapamycin is a potent allosteric mTORC1 inhibitor with clinical applications as an anticancer agent. However, only a fraction of cancer patients responds to the drug, and no biomarkers are available to predict tumor sensitivity. Recently, we and others have obtained evidence for potential involvement of tropomyosin-related kinase (TRK) receptor protein tyrosine kinases (TRKA, TRKB, TRKC) in leukemia. In the present study, we tested the therapeutic effect of Rapamycin and its analog RAD001 on altered TRK-induced leukemia in a murine model. Daily treatment with Rapamycin (2 mg/kg) or RAD001 (1 mg/kg) significantly prolonged the survival of treated animals (n = 40) compared with the placebo group. Consistently, both mTOR and S6 proteins were strongly dephosphorylated in vitro and in vivo after treatment with Rapamycin or RAD001. However, Rapamycin did not completely inhibit mTORC1-dependent phosphorylation of 4E-BP1. With exception of one mouse showing slight reactivation of Akt after treatment, no reactivation of MAPK or Akt pathways was observed in other resistant tumors. Interestingly, leukemic cells isolated from a Rapamycin-resistant mouse were still highly sensitive to Rapamycin in vitro. Our findings suggest that altered TRK signaling may be a good predictor of tumor sensitivity to mTOR inhibition and that pathways other than MAPK and Akt exist that may trigger resistance of leukemic cells to Rapamycin in vivo.
authors.affiliation: Department of Experimental Hematology, Hannover Medical School, Carl-Neuberg-Strasse 1, Hannover, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Rhein
authors.forename: Adrian
authors.initials: A
authors.lastname: Schwarzer
authors.forename: Min
authors.initials: M
authors.lastname: Yang
authors.forename: Volkhard
authors.initials: V
authors.lastname: Kaever
authors.forename: Martijn
authors.initials: M
authors.lastname: Brugman
authors.forename: Johann
authors.initials: J
authors.lastname: Meyer
authors.forename: Arnold
authors.initials: A
authors.lastname: Ganser
authors.forename: Christopher
authors.initials: C
authors.lastname: Baum
authors.forename: Zhixiong
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004790:Enzyme Induction / Q000187:drug effects; D000068338:Everolimus; D006801:Humans; D007942:Leukemia, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D046912:Multiprotein Complexes; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D016019:Survival Analysis; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D019208:Brain-Derived Neurotrophic Factor; D046912:Multiprotein Complexes; D011506:Proteins; D000068338:Everolimus; C546842:MTOR protein, human; D020813:Receptor, trkB; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus