Molecular mechanisms of resistance to therapies targeting the epidermal growth factor receptor.
Targeted therapies that inhibit the activity of tyrosine kinase receptors such as the epidermal growth factor receptor (EGFR) have shown activity against solid malignancies when used as single agents or in combination with chemotherapy. Although anti-EGFR therapies are active in some patients, eventually disease in nearly all patients will become refractory to therapy. Therefore, a better understanding of the mechanisms of resistance to anti-EGFR therapies is critical to further improve the efficacy of this class of agents. Mechanisms that mediate resistance to anti-EGFR therapies include the presence of redundant tyrosine kinase receptors, increased angiogenesis, and the constitutive activation of downstream mediators. Two recent landmark publications have also shown that specific mutations in the kinase domain of EGFR in some lung carcinomas are associated with markedly improved response rates to an EGFR tyrosine kinase inhibitor. Mutations in the EGFR receptor seem to play a significant role in determining the sensitivity of tumor cells to EGFR inhibitor therapy by altering the conformation and activity of the receptor. As the field of molecular therapeutics continues to evolve, a comprehensive understanding of resistance mechanisms will ultimately lead to refinements in our regimens to provide better care for patients with cancer.
Camp
E Ramsay
ER
Department of Surgical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030-4009, USA.
Summy
Justin
J
Bauer
Todd W
TW
Liu
Wenbiao
W
Gallick
Gary E
GE
Ellis
Lee M
LM
D002277:Carcinoma / Q000473:pathology*; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D006801:Humans; D008024:Ligands; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008954:Models, Biological; D009154:Mutation; D009389:Neovascularization, Pathologic; D017434:Protein Structure, Tertiary; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000188:drug therapy; D013997:Time Factors; D016896:Treatment Outcome
D008024:Ligands; D066246:ErbB Receptors