Molecular Pathways Molecular Pathways: BCR-ABL

Aberrant tyrosine kinase activity plays a critical role in many hematologic disorders, including chronic myeloid leukemia characterized by the constitutive activity of BCR-ABL. ABL therefore represents a crucial target for new therapeutic strategies. Here, we summarize the molecular pathways that are abnormally activated by the oncoprotein. Such pathways may provide additional opportunities to develop new drugs to overcome the resistance to tyrosine kinase inhibitors. In particular, the phosphoinositide 3-kinase (PI3K)/AKTpathway canbe effectively blockedbymTOR inhibitors, and several compounds canhit theRAS pathway and the resulting mitogen-activated protein (MAP) extracellular signal-regulated kinase (ERK)1/2 (MEK) andMAPkinase activation. Furthermore,mitotic kinases can be blocked byAurora kinase inhibitors, and Pim kinases can be blocked by selective serine-threonine kinase inhibitors. Finally, the abnormal pathways that sustain the self-renewal of leukemic stem cells are described as possible targets to completely eradicate leukemic clones. Such pathways include the Hedgehog pathway, which can be blocked by Smoothened inhibitors, and the CXCR4/SDF1 axis, which can be targeted by specific antagonists. Clin Cancer Res; 18(4); 930–7. 2011 AACR.