Leukemias induced by altered TRK-signaling are sensitive to mTOR inhibitors in preclinical models
- نوع فایل : کتاب
- زبان : انگلیسی
- مؤلف : Mathias Rhein & Adrian Schwarzer & Min Yang & Volkhard Kaever & Martijn Brugman & Johann Meyer & Arnold Ganser & Christopher Baum & Zhixiong Li
- چاپ و سال / کشور: 2010
Description
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.
Ann Hematol (2011) 90:283–292 DOI 10.1007/s00277-010-1065-3 Received: 17 August 2010 / Accepted: 20 August 2010 / Published online: 7 September 2010
