title: Receptor tyrosine kinase (RTK) inhibition is effective in chemosensitising EGFR-expressing drug resistant human ovarian cancer cell lines when used in combination with cytotoxic agents.
abstract: This study has focused on the use of RTK inhibitors in the treatment of ovarian cancer. We have used the human ovarian cancer cell line PEO1 alongside two in-house derived drug resistant variants: PEO1CarboR (8-fold acquired resistance to carboplatin and cisplatin) and the Pgp expressing PEO1TaxR (15-fold acquired resistance to paclitaxel). These variant cell lines were shown to have a higher expression of EGFR 1.6- and 2.0-fold increase, respectively, compared with the parental cell line. We have shown that the RTK inhibitor GW282974A (an analogue of GW2016; lapatinib) is effective in chemosensitisation of drug resistant EGFR over-expressing cells giving rise to a synergistic effect when used in combination with either cisplatin or paclitaxel in chemosensitivity assays. These effects were also seen at the level of apoptosis using the Annexin V assay and expression levels of the IAP Survivin. A reduction in the downstream signalling effector phosphorylated ERK was seen in both resistant cell lines when GW282974A was used in combination with either cisplatin or paclitaxel. This reduction was not so apparent in cells treated with the single agent GW282974A or cytotoxic agent. Interestingly, we did not show evidence for an enhanced sensitivity to the RTK inhibitor in our EGFR expressing resistant lines versus parental PEO1 cells. However, the paclitaxel resistant cell line appeared more sensitive to the chemosensitising effects of GW282974A, in line with its increased EGFR expression. Our data suggest that RTK inhibition is effective in circumvention of tumour cell drug resistance that occurs in conjunction with EGFR overexpression.
authors.affiliation: Oncology Division, Room 26PGM02, Postgraduate Medical School, University of Surrey, Daphne Jackson Road, Manor Park, Guildford, Surrey GU2 7WG, UK. H.Coley@surrey.ac.uk
authors.forename: Helen M
authors.initials: HM
authors.lastname: Coley
authors.forename: Christine F
authors.initials: CF
authors.lastname: Shotton
authors.forename: Abi
authors.initials: A
authors.lastname: Ajose-Adeogun
authors.forename: Helmout
authors.initials: H
authors.lastname: Modjtahedi
authors.forename: Hilary
authors.initials: H
authors.lastname: Thomas
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D017239:Paclitaxel / Q000008:administration & dosage; D011799:Quinazolines / Q000008:administration & dosage; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D000077022:Survivin
chemical_list: D000970:Antineoplastic Agents; C107489:BIRC5 protein, human; D004791:Enzyme Inhibitors; C506645:GW2974; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D011799:Quinazolines; D000077022:Survivin; D066246:ErbB Receptors; D020794:Receptor Protein-Tyrosine Kinases; D019950:Mitogen-Activated Protein Kinase 1; D017239:Paclitaxel