{"@context":"https://schema.org","@type":"ScholarlyArticle","headline":"Abstract 4453: Development and characterisation of AZD-8931-resistant HER-2 positive breast cancer cells.","author":[{"@type":"Person","name":"H. Creedon"},{"@type":"Person","name":"M. Muir"},{"@type":"Person","name":"L. Hayward"},{"@type":"Person","name":"V. Brunton"}],"datePublished":"2013","isPartOf":{"@type":"Periodical","name":"Cancer Research"},"identifier":"https://doi.org/10.1158/1538-7445.AM2013-4453","description":"Abstract\n The introduction of HER-2 directed therapies has revolutionised the management of both early and advanced HER-2 positive breast cancer. However, despite significant improvements in treatment outcomes, both inherent and acquired resistance are frequently encountered problems. Emerging evidence from early phase neo-adjuvant clinical trials, such as Neo-sphere and Neo-ALTTO, suggests that targeting multiple members of the Human epidermal growth factor receptor (HER) family is more efficacious than single target inhibition. AZD 8931 is a novel equipotent reversible tyrosine kinase inhibitor of EGFR, HER-2 and HER-3 signalling with proven pre-clinical efficacy in breast, head and neck and non-small cell lung cancers {1}.\n To investigate potential mechanisms of acquired resistance to AZD-8931, HER-2 amplified SKBR-3 breast cancer cells were rendered resistant by culture with escalating doses of drug. Resistant and parental cell lines were phenotypically distinct with resistance being associated with greater cell spreading and increased cell density. Cross resistance to lapatinib, a reversible dual EGFR/HER 2 tyrosine kinase inhibitor, was demonstrated with an over 50 fold increase in IC50. Signalling changes associated with a resistant phenotype were explored with a combination of Reverse Phase Protein Array (RPPA) and western blotting. Following drug treatment, resistant cells still displayed a dose-dependent reduction in phospho HER-2 (Tyr 1248)/EGFR (Tyr 1173). However, constitutive activation of the HER 3 pathway resulted in persistent downstream signalling via the PI3K/AKT pathway and increased cell survival.\n Tumorigenesis in the MMTV-Nic model is driven by mammary-specific expression of a constitutively active HER 2 transgene {2}. This model has been crossed with a strain with a floxed PTEN allele {2} and studies are currently under way to explore the role of PTEN in AZD-8931 resistance.\n Citation Format: Helen Creedon, Morwenna Muir, Larry Hayward, Valerie Brunton. Development and characterisation of AZD-8931-resistant HER-2 positive breast cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4453. doi:10.1158/1538-7445.AM2013-4453","url":"https://innscience.ca/en/community/literature/848c69f4-2c7d-4da6-94a1-da3e4eb72e72"}