Src-family kinases in the development and therapy of Philadelphia chromosome-positive chronic myeloid leukemia and acute lymphoblastic leukemia

Abstract

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 (Phþ 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 imatinibresistant 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) andindependent 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 Phþ ALL, as well as the potential role of dual SFK/BCR-ABL inhibition in the management of these diseases.

Lyn Kinase-Dependent Regulation of miR181 and Myeloid Cell Leukemia-1 Expression: Implications for Drug Resistance in Myelogenous Leukemia

“…Inhibition of Lyn with SFK inhibitors reduced prosurvival signaling and reversed imatinib resistance in CML cells (Ito et al, 2007;Nam et al, 2007). Moreover, the dual-specificity BCR-Abl/SFK inhibitors (i.e., dasatinib, sorafenib, nilotinib) effectively treat patients who are nonresponsive to imatinib therapy (Li, 2008;Wu et al, 2008).…”

“…However, despite the success of imatinib for the treatment of chronic myelogenous leukemia (CML) and other cancers, multiple mechanisms of imatinib resistance have been identified. These include BCR-Abl mutations that prevent imatinib binding (i.e., T315I) (Hochhaus et al, 2002;Yamamoto et al, 2004), BCRAbl overexpression (Hochhaus et al, 2002), and increased expression and activity of Src family kinases (SFKs) or other prosurvival proteins (Illmer et al, 2004;Li, 2008). Lyn kinase (Lyn) has been implicated in imatinib resistance in both CML cells and patient samples.…”

From Hen House to Bedside: Tracing Hanafusa's Legacy from Avian Leukemia Viruses to SRC to ABL and Beyond

“…54 A mutation in BCR-ABL within a target residue of the src family kinases can lead to resistance to therapy. 46,56 …”

“…46,47 BCR-ABL and Src family members Hck and Lyn physically interact with each other and play a key role in leukemogenesis. [48][49][50] The SH2, SH3, and C-terminal domain of BCR-ABL can interact with Hck, 51 which can in return phosphorylate the SH2, SH3, and Grb2 binding site.…”

New drugs in the therapy of multiple myeloma

“…In these settings the pathogenetic role of many members of the Src family has been demonstrated, such as the overexpression of Lyn. 14,15 The Src kinases family comprises nine non-receptor tyrosine kinases (SRC, FYN, YES, BLK, YRK, FGR, HCK, LCK, LYN). 16 Some Src members are ubiquitously expressed, whereas others display tissuespecific expression patterns.…”