title: Inductive mechanisms limiting response to anti-epidermal growth factor receptor therapy.
abstract: Aberrant epidermal growth factor receptor (EGFR) signalling, a key feature of a variety of human malignancies, can drive a range of mechanisms underlying tumour growth and progression, including increased cell proliferation, angiogenesis, metastasis and decreased apoptosis. Anti-EGFR therapies, as monotherapies and in combination with chemotherapy, have proved effective in inhibiting these processes both in the clinical and in the preclinical settings. However, only a small cohort of patients have derived significant benefit from this therapy, with both de novo and acquired resistance to these agents evident in a number of recent studies. If we are to improve the effectiveness of such targeted therapies, then there is an urgent need to understand the resistance mechanisms. Here, we describe both non-genomic and genomic mechanisms of resistance to the selective EGFR tyrosine kinase inhibitor gefitinib (IRESSA), which we have identified initially in an EGFR-positive tamoxifen-resistant MCF-7 breast cancer cell line, but more recently in other EGFR-positive cancer types. Importantly, we show that gefitinib, in common with anti-hormonal agents, is not a passive bystander in the cellular response to drug treatment, but plays an active role in promoting signalling pathways that serve to limit its anti-tumour activity and maintain the cellular cohort from which acquired resistance can ultimately evolve. These findings indicate that inductive signalling is an important determinant of response to EGFR-targeted therapies and deciphering such pathways may provide us with the opportunity to design more effective strategies to combat resistance mechanisms and improve response to initial therapy.
authors.affiliation: Tenovus Centre for Cancer Research, Welsh School of Pharmacy, Cardiff University, Redwood Building, King Edward VII Avenue, Cardiff CF10 3XF, UK. hutchesonir@cf.ac.uk
authors.forename: Iain R
authors.initials: IR
authors.lastname: Hutcheson
authors.forename: Janice M
authors.initials: JM
authors.lastname: Knowlden
authors.forename: Helen E
authors.initials: HE
authors.lastname: Jones
authors.forename: Rajpal S
authors.initials: RS
authors.lastname: Burmi
authors.forename: Richard A
authors.initials: RA
authors.lastname: McClelland
authors.forename: Denise
authors.initials: D
authors.lastname: Barrow
authors.forename: Julia M W
authors.initials: JM
authors.lastname: Gee
authors.forename: Robert I
authors.initials: RI
authors.lastname: Nicholson
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics*; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D051058:Oncogene Protein v-akt / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010750:Phosphoproteins / Q000502:physiology; D011799:Quinazolines / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics
chemical_list: D018931:Antineoplastic Agents, Hormonal; C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins; D011799:Quinazolines; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D051058:Oncogene Protein v-akt; D000077156:Gefitinib