title: Predicting tumour response to anti-HER1 therapy using medical imaging: a literature review and in vitro study of [18F]-FDG incorporation by breast cancer cells responding to cetuximab.
abstract: Cetuximab, an anti-HER1 (EGFR) antibody, is currently under trial for the treatment of breast cancer. HER1 expression is not necessarily a predictor of response to cetuximab as mutant components of the pathways activated by HER1 which include PI3K/Akt can lead to resistance. Techniques that monitor events downstream of HER1 are more likely to provide an accurate measure of the efficacy of an anti-HER1 treatment. Glucose metabolism has been shown to be strongly influenced by the state of activation of PI3K/Akt. Here, the association between [18F]-FDG incorporation in breast cancer cells during response to cetuximab is investigated. The study also reviews the development of medical imaging probes that target HER1 The sensitivity to cetuximab of three breast tumour cell lines, SKBr3, MDA-MB-453 and MDA-MB-468, expressing HER1 at low and high levels, are determined using an MTT assay over a six-day period and a clonogenic assay carried out after seven- and 10-day exposures. Incorporation of FDG by cells treated with growth inhibitory doses of cetuximab were carried out after 4 hand two, four and six days of treatment. Glucose transport (rate of uptake of the non-metabolisable analogue [3H]o-methyl-D-glucose), hexokinase activity and lactate production were measured on cells treated with inhibitory doses of cetuximab for six days. The IC50, dose for MDA-MB-468 cells and the IC10 (maximum achievable inhibition) doses for MDA-MB-543 and SKBr3 treated with cetuximab for six days were 2.6, 5 and 148 microg/mL, respectively. Incorporation of FDG by SKBr3 and MDA-MB-453 cells was found to be decreased by MDA-MB468 cells using IC50, and IC20, doses of cetuximab for six days. Lactate production was found to be increased by MDA-MB-468 cells responding to cetuximab. Incorporation of FDG at the tumour cell level is modulated by treatment with growth inhibitory doses of cetuximab in cells sensitive to cetuximab due to modulation of HK activity.
authors.affiliation: Aberdeen Biomedical Imaging Centre, School of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD. t.smith@abdn.ac.uk
authors.forename: T A D
authors.initials: TA
authors.lastname: Smith
authors.forename: R W
authors.initials: RW
authors.lastname: Cheyne
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D000068818:Cetuximab; D003114:Colony-Forming Units Assay; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D006593:Hexokinase / Q000378:metabolism; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D049268:Positron-Emission Tomography; D013778:Tetrazolium Salts; D013844:Thiazoles
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D013778:Tetrazolium Salts; D013844:Thiazoles; D019788:Fluorodeoxyglucose F18; D019344:Lactic Acid; D006593:Hexokinase; C512478:EGFR protein, human; D066246:ErbB Receptors; C022616:thiazolyl blue; D005947:Glucose; D000068818:Cetuximab