Constitutive tyrosine kinase (TK) activity of p210 bcr-abl fusion protein is the causative event of Chronic Myeloid Leukemia (CML). Accordingly, its inhibition abrogates the proliferative advantage and apoptosis resistance of clonal leukemic progenitors and induces the disease remission and the emergence of normal hematopoiesis. Imatinib mesylate (IM), the first TK inhibitor approved for clinical use in CML, let to hope to have a cure for Ph1-(bcr-abl)-positive leukemias. Unfortunaley, the IM resistance apparent from longer clinical follow-up emerged as the drug major limitation. It imposes the development of combined therapies capable of targeting genes located downstream of bcr-abl and endowed with a bcr-abl-independent role in CML progression towards the fully transformed phenotype of blast crisis. Src kinase inhibitors are now regarded as the most promising drugs as they target p210 constitutive phosphorylation at Tyr177. We investigated the in vitro effects of a new compound, a 4-anilino-3-quinolinecarbonitrile (SKI-606) alone or in combination with IM on proliferation and survival of bcr-abl-transducing 32D cell clones. Here we demonstrate that SKI606 and IM combined treatment is more effective than IM alone in inhibiting the enzymatic activity of Cdk2, the cyclin-dependent kinase mostly responsible for p210 TK-induced acceleration of cell cycle progression. Cdk2 activity was prevented by the enhanced effects of drug combination on Chk2-Cdc25A axis and PI3K/Akt pathway (leading to increased nuclear import of Cdk inhibitors p21 and p27 and to cyclin D downmodulation). Drug combination effects on Chk2-Cdc25A and PI3K/Akt were greater in IM-sensitive bcr-abl-expressing cells compared to IM-resistant cells and were abrogated by IL3. In conclusion, the combined use of TK and Src kinase inhibitors may prevent IM resistance and, therefore, improve the prognosis of CML at clinical diagnosis, but its advantage in the treatment of IM-resistant CML is likely marginal and conditional upon the mechanisms responsible for IM resistance
M. Mancini, G. Brusa, E. Zuffa, T. Graffone, F. Pennisi, N. Calonghi, et al. (2005). NEW STRATEGIES IN THE TREATMENT OF CHRONIC MYELOID LEUKEMIA. COMBINED USE OF SRC AND TYROSINE KINASE INHIBITORS CIRCUMVENTS THE DEVELOPMENT OF DRUG-RESISTANCE. SIENA : Tipografia Senese.
NEW STRATEGIES IN THE TREATMENT OF CHRONIC MYELOID LEUKEMIA. COMBINED USE OF SRC AND TYROSINE KINASE INHIBITORS CIRCUMVENTS THE DEVELOPMENT OF DRUG-RESISTANCE
MANCINI, MANUELA;BRUSA, GIANLUCA;ZUFFA, ELISA;CALONGHI, NATALIA;MASOTTI, LANFRANCO;SANTUCCI, MARIA ALESSANDRA
2005
Abstract
Constitutive tyrosine kinase (TK) activity of p210 bcr-abl fusion protein is the causative event of Chronic Myeloid Leukemia (CML). Accordingly, its inhibition abrogates the proliferative advantage and apoptosis resistance of clonal leukemic progenitors and induces the disease remission and the emergence of normal hematopoiesis. Imatinib mesylate (IM), the first TK inhibitor approved for clinical use in CML, let to hope to have a cure for Ph1-(bcr-abl)-positive leukemias. Unfortunaley, the IM resistance apparent from longer clinical follow-up emerged as the drug major limitation. It imposes the development of combined therapies capable of targeting genes located downstream of bcr-abl and endowed with a bcr-abl-independent role in CML progression towards the fully transformed phenotype of blast crisis. Src kinase inhibitors are now regarded as the most promising drugs as they target p210 constitutive phosphorylation at Tyr177. We investigated the in vitro effects of a new compound, a 4-anilino-3-quinolinecarbonitrile (SKI-606) alone or in combination with IM on proliferation and survival of bcr-abl-transducing 32D cell clones. Here we demonstrate that SKI606 and IM combined treatment is more effective than IM alone in inhibiting the enzymatic activity of Cdk2, the cyclin-dependent kinase mostly responsible for p210 TK-induced acceleration of cell cycle progression. Cdk2 activity was prevented by the enhanced effects of drug combination on Chk2-Cdc25A axis and PI3K/Akt pathway (leading to increased nuclear import of Cdk inhibitors p21 and p27 and to cyclin D downmodulation). Drug combination effects on Chk2-Cdc25A and PI3K/Akt were greater in IM-sensitive bcr-abl-expressing cells compared to IM-resistant cells and were abrogated by IL3. In conclusion, the combined use of TK and Src kinase inhibitors may prevent IM resistance and, therefore, improve the prognosis of CML at clinical diagnosis, but its advantage in the treatment of IM-resistant CML is likely marginal and conditional upon the mechanisms responsible for IM resistanceI documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
