Reversing resistance to targeted therapy.
The development of molecular targeted anticancer drugs is rapidly changing cancer therapeutics. However, drug resistance to these novel agents remains a real clinical concern. Reports now indicate that resistance to many of these molecular targeted agents--including hormone therapies, trastuzumab, imatinib, and gefitinib--occurs via common resistance mechanisms. These include 1) inadequate target blockade due to sub-optimal drug delivery; 2) altered target expression at the DNA (gene amplification), mRNA or protein level; 3) an altered target such as a mutated kinase domain; 4) modified target regulating proteins (e.g. altered expression of co-activators and/or co-repressors for nuclear steroid hormone receptors); 5) signalling by alternative proteins (functional redundancy) or different signalling pathways. It is envisioned that the molecular evaluation of clinical anticancer drug resistance, which requires the detailed study of pharmacokinetics, pharmacogenetics and pharmacodynamics, will allow the development of rational reversal strategies and improved patient outcome.
Vidal
L
L
Institute of Cancer Research and Royal Marsden Hospital, Sutton, UK.
Attard
G
G
Kaye
S
S
De Bono
J
J
D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000009:adverse effects / Q000627:therapeutic use; D001549:Benzamides; D016503:Drug Delivery Systems; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D000077156:Gefitinib; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use; D011799:Quinazolines / Q000009:adverse effects / Q000627:therapeutic use; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D000068878:Trastuzumab
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018931:Antineoplastic Agents, Hormonal; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D011799:Quinazolines; D000068877:Imatinib Mesylate; D000068878:Trastuzumab; D000077156:Gefitinib