title: Targeting focal adhesion kinase in ER+/HER2+ breast cancer improves trastuzumab response.
abstract: The HER2 transmembrane receptor is a well-characterised predictive marker for trastuzumab benefit and may be associated with decreased benefit from endocrine therapy use. Despite the clinical effectiveness of anti-HER2 agents in such cases, resistance represents a significant limiting factor. Focal adhesion kinase (FAK) plays an important role in HER2 signalling, mediating downstream Akt activation in addition to HER2 cross talk with other growth factor receptors. In this study, we investigated the therapeutic potential of FAK in oestrogen receptor-positive (ER+)/HER2+ breast cancer using the novel FAK-specific inhibitor PF4554878 ('PF878'). The activation of the FAK/HER2 signalling pathway was assessed in ER+/HER2- (MCF7 and T47D) and ER+/HER2+ (BT-474 and MDAMB361) breast cancer cells in the presence or absence of PF878 and PF878±trastuzumab. The effects of PF878 on cell growth as a monotherapy and in combination with trastuzumab were assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and Coulter counting with isobologram analysis to determine synergy/additive effects. FAK activation (at Y861 but not at Y397) was highest in ER+/HER2+ cells, which also demonstrated the greatest sensitivity to PF878. As a monotherapy, PF878 prevented heregulin-induced MDA361 cell migration, but had no significant effect on cell growth. The treatment of ER+/HER2+ cells with PF878 and trastuzumab in combination resulted in the synergistic inhibition of cell proliferation. Underlying this was an abrogation of Akt activity and increased poly(ADP-ribose) polymerase cleavage, effects that were greatest in trastuzumab-refractory MDA361 cells. Collectively, these data support a role for FAK in ER+/HER2+ breast cancer, where its targeting has the potential to improve trastuzumab response. This is particularly important in the context of ER+/HER2+, trastuzumab-refractory disease, where FAK inhibition may present an important strategy to restore trastuzumab sensitivity.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Cardiff University, Wales, UK.
authors.forename: Glorianne
authors.initials: G
authors.lastname: Lazaro
authors.forename: Chris
authors.initials: C
authors.lastname: Smith
authors.forename: Lindy
authors.initials: L
authors.lastname: Goddard
authors.forename: Nicola
authors.initials: N
authors.lastname: Jordan
authors.forename: Richard
authors.initials: R
authors.lastname: McClelland
authors.forename: Peter
authors.initials: P
authors.lastname: Barrett-Lee
authors.forename: Robert I
authors.initials: RI
authors.lastname: Nicholson
authors.forename: Stephen
authors.initials: S
authors.lastname: Hiscox
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D051417:Focal Adhesion Kinase 1; D047428:Protein Kinase Inhibitors; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C496050:PTK2 protein, human
keywords: HER2; breast cancer; focal adhesion kinase; human epidermal growth factor receptor 2; luminal B breast cancer; trastuzumab