Targeting the EGFR pathway for cancer therapy.
Clinical studies have shown that HER-2/Neu is over-expressed in up to one-third of patients with a variety of cancers, including B-cell acute lymphoblastic leukemia (B-ALL), breast cancer and lung cancer, and that these patients are frequently resistant to conventional chemo-therapies. Additionally, in most patients with multiple myeloma, the malignant cells over-express a number of epidermal growth factor receptors (EGFR)s and their ligands, HB-EGF and amphiregulin, thus this growth-factor family may be an important aspect in the patho-biology of this disease. These and other, related findings have provided the rationale for the targeting of the components of the EGFR signaling pathways for cancer therapy. Below we discuss various aspects of EGFR-targeted therapies mainly in hematologic malignancies, lung cancer and breast cancer. Beside novel therapeutic approaches, we also discuss specific side effects associated with the therapeutic inhibition of components of the EGFR-pathways. Alongside small inhibitors, such as Lapatinib (Tykerb, GW572016), Gefitinib (Iressa, ZD1839), and Erlotinib (Tarceva, OSI-774), a significant part of the review is also dedicated to therapeutic antibodies (e.g.: Trastuzumab/Herceptin, Pertuzumab/Omnitarg/rhuMab-2C4, Cetuximab/Erbitux/IMC-C225, Panitumumab/Abenix/ABX-EGF, and also ZD6474). In addition, we summarize, both current therapy development driven by antibody-based targeting of the EGFR-dependent signaling pathways, and furthermore, we provide a background on the history and the development of therapeutic antibodies.
Johnston
James B
JB
Department of Internal Medicine, Manitoba Institute of Cell Biology, ON6010-675 McDermot Ave. , University of Manitoba, Winnipeg, MB, R3E 0V9, Canada.
Navaratnam
Sri
S
Pitz
Marshall W
MW
Maniate
Jerry M
JM
Wiechec
Emilia
E
Baust
Heinrich
H
Gingerich
Joel
J
Skliris
Georgios P
GP
Murphy
Leigh C
LC
Los
Marek
M
D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D016503:Drug Delivery Systems / Q000379:methods*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008024:Ligands; D009369:Neoplasms / Q000188:drug therapy*
D000911:Antibodies, Monoclonal; D008024:Ligands; D066246:ErbB Receptors