Novel targeted therapies for Bcr-Abl positive acute leukemias: beyond STI571.
In the pathophysiology of CML, the constitutive activity of the Bcr-Abl tyrosine kinase (TK) is, most likely, the sole molecular abnormality of the chronic phase. It also remains a critical molecular determinant of malignant behavior of the leukemic progenitors in the accelerated and blastic phase of CML. Therefore, downregulation of the levels and activity of Bcr-Abl is clearly the lynchpin of a rational therapeutic strategy against all phases of CML. Support for this has only been strengthened by the observations that resistance to imatinib mesylate (imatinib) commonly involves a breakthrough and the persistent activity of Bcr-Abl TK. This is due to either mutations that inhibit imatinib action on Bcr-Abl TK or amplification of the bcr-abl gene. Recent studies have demonstrated that other small molecule tyrosine kinase inhibitors that also inhibit Bcr-Abl TK may be highly active in inducing differentiation and apoptosis of CML progenitors, regardless of their sensitivity to imatinib. Small molecule inhibitors that downregulate the levels of Bcr-Abl by inhibiting its translation, e.g., arsenic trioxide, or promoting its proteasomal degradation, e.g., geldanamycin analogues, have also been identified. Finally the identification of other potent survival and antiapoptotic signaling pathways in imatinib-resistant CML progenitors indicates that inhibitors of these pathways will eventually be treatment strategies for advanced phases of CML.
Nimmanapalli
Ramadevi
R
Department of Interdisciplinary Oncology, University of South Florida, Tampa, Florida , USA.
Bhalla
Kapil
K
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D015536:Down-Regulation; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism; D010879:Piperazines / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011743:Pyrimidines / Q000627:therapeutic use*
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl