High Affinity Molecules Disrupting GRB2 Protein Complexes as a Therapeutic Strategy for Chronic Myelogenous Leukaemia

A review. Chronic myelogenous leukemia (CML) is one of the most intensively studied human malignancies. It has been the focus of major efforts to develop potent drugs for several decades, but until recently cure rates remained low. A breakthrough in CML therapy was very likely accomplished with the clin. introduction of STI-571 in 2000/2001. Despite the hope that STI-571 has generated for many CML patients, development of resistance to this drug is already apparent in some cases, esp. if the CML is diagnosed in its later stages. Therefore, novel drugs which can be used alone or in combination with STI-571 are highly desirable. This review briefly summarizes the current understanding and therapy of CML and then discusses in more detail basic lab. research that attempts to target Grb2, an adaptor protein known to directly interact with the Bcr portion of the Bcr-Abl fusion protein. Blocking the binding of Grb2 to the GDP-releasing protein SOS is well known to abrogate the activation of the GTPase Ras, a major driving force of the central mitogenic (MAP kinase) pathway. Addnl. Grb2 effector proteins may also contribute to the proliferation-inhibiting effects obsd. upon uncoupling Grb2 from its downstream signaling system. Since Grb2 is a known signal transducer for several major human oncogenes, this approach may have applications for a wider range of human cancers. [on SciFinder (R)]