Stem cell and kinase activity-independent pathway in resistance of leukaemia to BCR-ABL kinase inhibitors.
BCR-ABL tyrosine kinase inhibitors, such as imatinib (Gleevec) are highly effective in treating human Philadelphia chromosome-positive (Ph+) chronic myeloid leukaemia (CML) in chronic phase but not in terminal acute phase; acquired drug resistance caused mainly by the development of BCR-ABL kinase domain mutations prevents cure of the leukaemia. In addition, imatinib is ineffective in treating Ph+ B-cell acute lymphoblastic leukaemia (B-ALL) and CML blast crisis, even in the absence of the kinase domain mutations. This type of drug resistance that is unrelated to BCR-ABL kinase domain mutations is caused by the insensitivity of leukaemic stem cells to kinase inhibitors such as imatinib and dasatinib, and by activation of a newly-identified signalling pathway involving SRC kinases that are independent of BCR-ABL kinase activity for activation. This SRC pathway is essential for leukaemic cells to survive imatinib treatment and for CML transition to lymphoid blast crisis. Apart from BCR-ABL and SRC kinases, stem cell pathways must also be targeted for curative therapy of Ph+ leukaemia.
Li
Shaoguang
S
The Jackson Laboratory, Bar Harbor, ME, USA. shaoguang.li@jax.org
Li
Dongguang
D
D000818:Animals; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000201:enzymology*; D014411:Neoplastic Stem Cells / Q000201:enzymology*; D010677:Philadelphia Chromosome; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*
D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl