[Targeting of membrane receptor tyrosine kinases: is there resistance in the HER?].
Human Epidermal growth factor Receptors (HER) play an important role in cellular proliferation, and differentiation. Their overexpression in tumor tissues is often associated with a poor prognosis. Consequently, HER receptors are interesting therapeutic targets for cancer treatment. Two strategies are proposed. First, monoclonal antibodies can be used to inhibit the binding of one ligand to its receptor. The second approach is based upon the designing of tyrosine kinase inhibitors capable to bind into the phosphorylation site of the receptor. Consequently, both approaches block the signal transduction downstream. Resistance to anti receptor tyrosine kinase therapy can lead to enhanced morbidity associated with high therapeutic cost. Different mechanisms can be implicated. Non specific mechanisms include alterations of the signal transduction pathways (PI3K/AKT), recruitment of alternative receptor tyrosine kinase pathways (IGFR, VEGFR) and proteasome degradation inhibition. Other mechanisms are specific to HER and rely on inhibition of the binding of monoclonal antibodies (sialomucin-MUC4), heterodimerisation of HER, truncated soluble receptors intervention and mutated variants, as demonstrated very recently with EGF receptors, or genetic polymorphism. This paper reviews these different resistance mechanisms that have been identified in preclinical and clinical situations.
Monnier
Lucile
L
Centre Alexis-Vautrin, Unité de biologie des tumeurs, EA3452, avenue de Bourgogne, 54511 Vandoeuvre-lès-Nancy Cedex.
Milano
Gérard
G
Penault-Llorca
Frédérique
F
Merlin
Jean-Louis
JL
D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D055264:Mucin-4; D009077:Mucins / Q000378:metabolism; D009369:Neoplasms / Q000209:etiology / Q000378:metabolism / Q000628:therapy*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D066247:Receptor, ErbB-4; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D040262:Receptors, Vascular Endothelial Growth Factor / Q000378:metabolism; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D066246:ErbB Receptors; D007334:Insulin-Like Growth Factor I; D055264:Mucin-4; D009077:Mucins; D046988:Proteasome Endopeptidase Complex; D011505:Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D066247:Receptor, ErbB-4; D017526:Receptor, IGF Type 1; D040262:Receptors, Vascular Endothelial Growth Factor; D042461:Vascular Endothelial Growth Factor A; C524658:MUC4 protein, human; C587689:ERBB4 protein, human