Src-family kinases in the development and therapy of Philadelphia chromosome-positive chronic myeloid leukemia and acute lymphoblastic leukemia.
The BCR-ABL kinase inhibitor imatinib has shown significant efficacy in chronic myeloid leukemia (CML) and is the standard front-line therapy for patients in chronic phase. However, a substantial number of patients are either primarily refractory or acquire resistance to imatinib. While a number of mechanisms are known to confer resistance to imatinib, increasing evidence has demonstrated a role for BCR-ABL-independent pathways. The Src-family kinases (SFKs) are one such pathway and have been implicated in imatinib resistance. Additionally, these kinases are key to the progression of CML and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). The dual SFK/BCR-ABL inhibitor dasatinib is now clinically available and has markedly greater potency compared with imatinib against native BCR-ABL and the majority of imatinib-resistant BCR-ABL mutants. Therefore, this agent, as well as other dual SFK/BCR-ABL inhibitors under development, could provide added therapeutic advantages by overcoming both BCR-ABL-dependent (i.e. BCR-ABL mutations) and -independent forms of imatinib resistance and delaying transition to advanced phase disease. In this review, we discuss the preclinical and clinical evidence demonstrating the involvement of SFKs in imatinib resistance and the progression of CML and Ph+ ALL, as well as the potential role of dual SFK/BCR-ABL inhibition in the management of these diseases.
Li
Shaoguang
S
The Jackson Laboratory, Bar Harbor, ME 04609, USA. shaoguang.li@jax.org
D001549:Benzamides; D019008:Drug Resistance, Neoplasm; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000209:etiology*; D010879:Piperazines / Q000627:therapeutic use; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000209:etiology*; D011743:Pyrimidines / Q000627:therapeutic use; D015398:Signal Transduction; D019061:src-Family Kinases / Q000502:physiology*
D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D019061:src-Family Kinases