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.