Leukemias induced by altered TRK-signaling are sensitive to mTOR inhibitors in preclinical models
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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.
KeywordsAcute leukemia mTOR TRKs Resistance
This study was supported by the Deutsche Krebshilfe (grants: 10-2090-Li I and 108245) and DFG excellence cluster REBIRTH. AS is a student of the PhD program for Molecular Medicine in Hannover Medical School. We are very grateful to Rena-Mareike Struß, Jessica Wenzl, and Thomas Neumann for technical assistance; Michael Morgan for critical reading of this paper; and Hans Grundtke, Jörg Frühauf, and Martin Werner (Radiotherapy, Hannover Medical School) for irradiation of animals.
Conflict of interest
Authors declare no competing financial interests.
- 14.Meyer J, Rhein M, Schiedlmeier B, Kustikova O, Rudolph C, Kamino K, Neumann T, Yang M, Wahlers A, Fehse B, Reuther GW, Schlegelberger B, Ganser A, Baum C, Li Z (2007) Remarkable leukemogenic potency and quality of a constitutively active neurotrophin receptor, deltaTrkA. Leukemia 21:2171–2180CrossRefPubMedGoogle Scholar
- 24.Nishioka C, Ikezoe T, Yang J, Gery S, Koeffler HP, Yokoyama A (2009) Inhibition of mammalian target of rapamycin signaling potentiates the effects of all-trans retinoic acid to induce growth arrest and differentiation of human acute myelogenous leukemia cells. Int J Cancer 125:1710–1720CrossRefPubMedGoogle Scholar
- 30.Carracedo A, Ma L, Teruya-Feldstein J, Rojo F, Salmena L, Alimonti A, Egia A, Sasaki AT, Thomas G, Kozma SC, Papa A, Nardella C, Cantley LC, Baselga J, Pandolfi PP (2008) Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer. J Clin Invest 118:3065–3074PubMedGoogle Scholar