Nonreceptor Tyrosine Kinases

Even though the non-RTKs represent less than 10% of the human kinome, they have already provided a number of valuable anticancer drug targets such as the Abl and Src families. While this review will attempt to cover the latter in detail, it is also important to highlight other kinases that are emerging as potential targets.

The Jak (Janus) and Fak (focal adhesion) kinase families are both characterized by containing an integrin-binding domain. Jak tyrosine kinases56 are activated by interleukins, and are often found to be constitutively active in hematopoietic malignancies,57 with a recent report describing a link to breast cancer.58 Fak is a substrate and binding partner of Src, and there is an emerging literature highlighting the ability of Fak to interact with downstream signaling pathways, causing both proliferation and evasion of apotosis.60 In contrast, Csk (C-terminal Src kinase) is a negative regulator for Src, and inhibition of the kinase results in increased cell migration and in vitro invasiveness.61 While less studied to date, Pyk2 (proline-rich tyrosine kinase 2) has been shown to regulate apoptosis in multiple myeloma cells,62 and may also act downstream from fibroblast growth factor receptor (FGFR-3).63 In breast carcinomas there is an emerging link between Brk (breast tumor kinase) activity and disease progression,64 while Syk (spleen tyrosine kinase) protein levels have an inverse correlation with survival and metastasis in this disease, suggesting that Syk acts as a tumor suppressor gene in breast epithelium.65 It is likely that the elucidation of the roles of other non-RTKs (including Btk (Bruton's tyrosine kinase),66 Fes tyrosine kinase,67 and Fer tyrosine kinase68) may provide additional targets for anticancer drugs.

Imatinib (Gleevec, Glivec, or STI571, 1) (Figure 2),50'69-71 an inhibitor of the Bcr-Abl tyrosine kinase, was one of the first small-molecule kinase inhibitors to reach the market, being approved for the treatment of CML in May 2001.

CML is a clonal disease of hematopoietic progenitor cells, and is characterized by progressive granulocytosis, marrow hypercellularity, and splenomegaly.72-75 The link between CML and Ph +, caused by a reciprocal translocation (between chromosomes 9 and 12) was made as long ago as 1960. Of the two fusion genes created by this transformation,77'78 the Bcr-Abl gene on the Philadelphia chromosome (22q-) encodes a 210 kDa protein with upregulated tyrosine kinase activity.79 By 1990, a transgenic mouse model had been developed that demonstrated that Bcr-Abl was a leukemic oncogene.80 Subsequently, Bcr-Abl has been shown to be present in 95% of patients diagnosed with CML, and is also found in 10-15% of patients with acute lymphoblastic leukemia (ALL).81 The clinical utility of imatinib in CML is now well established, and demonstrates that inhibition of a primary disease driver using a kinase inhibitor can result in significant clinical activity.

Imatinib 1

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