High affinity molecules disrupting GRB2 protein complexes as a therapeutic strategy for chronic myelogenous leukaemia.
Chronic myelogenous leukaemia (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 clinical introduction of STI-571 [imatinib mesylate; Gleevec (USA); Glivec (other countries)] 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, especially 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 summarises the current understanding and therapy of CML and then discusses in more detail basic laboratory 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. Additional Grb2 effector proteins may also contribute to the proliferation-inhibiting effects observed upon uncoupling Grb2 from its downstream signalling 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.
Feller
Stephan M
SM
Cell Signalling Group, Molecular Oncology Laboratory, Cancer Research UK, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK. stephan.feller@.cancer.org.uk
Tuchscherer
Gabriele
G
Voss
Jan
J
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001549:Benzamides; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D005544:Forecasting; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051380:GRB2 Adaptor Protein; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000378:metabolism; D046911:Macromolecular Substances; D051379:Mice; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010446:Peptide Fragments / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D020664:Son of Sevenless Proteins / Q000502:physiology; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000502:physiology; D018631:ras Proteins / Q000037:antagonists & inhibitors; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D051380:GRB2 Adaptor Protein; C495948:GRB2 protein, human; C495949:Grb2 protein, mouse; D046911:Macromolecular Substances; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D010879:Piperazines; D011506:Proteins; D011743:Pyrimidines; D020664:Son of Sevenless Proteins; D014157:Transcription Factors; D000068877:Imatinib Mesylate; D019869:Phosphatidylinositol 3-Kinases; D016044:Fusion Proteins, bcr-abl; D018631:ras Proteins; C038753:leptomycin B