Hsp90 Inhibitors for the Treatment of Chronic Myeloid Leukemia

Figure 1

Signaling pathways activated by BCR-ABL. (a) BCR-ABL activates GRB-2/SOS which in turn activates RAS. Active RAS activates RAF. Active RAF stimulates MEK1, which in turn activates ERK1/2. Activation of Ras pathway by BCR-ABL aids CML cells proliferation. On the other hand, activated GRB-2/SOS stimulates GAB2 which activates PI3-K pathway. (b) BCR-ABL phosphorylates adaptor proteins like CRK and CRKL leading to the activation of PI3-K. PI3-K phosphorylates PIP2 to PIP3 which in turn activates AKT. AKT inhibits p27 leading to CML cells proliferation. AKT phosphorylates MDM2, which in turn inhibit p53. AKT activates NFκB via phosphorylation of IKK and IkBα. AKT inhibits p-BAD. Activation of NFκB and inhibition of p53 and BAD by AKT evade apoptosis and promote CML cells survival. (c) BCR-ABL phosphorylates STAT5 which also aid in evading apoptosis of CML cells. (d) BCR-ABL phosphorylate cytoskeleton proteins resulting in increased cellular motility and reduced adhesion to extracellular matrix of bone marrow.