title: Combining AZD8931, a novel EGFR/HER2/HER3 signalling inhibitor, with AZD5363 limits AKT inhibitor induced feedback and enhances antitumour efficacy in HER2-amplified breast cancer models.
abstract: The phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signalling network is frequently de-regulated in breast cancer and has been shown to mediate resistance to anti-HER2 agents. Whilst constitutive activation of this pathway is emerging as a marker of sensitivity to various PI3K pathway inhibitors, activity of these agents in the clinic may be limited by the presence of feedback loops, leading to reactivation of receptor tyrosine kinases, such as HER2/HER3. To determine whether inhibition of HER2 could increase the efficacy of AZD5363, a novel AKT inhibitor, a panel of breast cancer cells was dosed with AZD5363 in combination with AZD8931, an inhibitor of EGFR/HER2/HER3 signalling. We show that the combined treatment resulted in synergistic growth inhibition and enhanced cell death, specifically in the HER2-amplified cell lines. Investigation of the mechanism by western blot analysis revealed that the addition of AZD8931 prevented the induction of HER2/HER3 phosphorylation induced by AZD5363 and resulted in concomitant inhibition of both the PI3K/AKT/mTOR and ERK signalling pathways and induction of apoptosis. Using the HCC1954 xenograft model, which is resistant to trastuzumab, we show that the combination of AZD5363 and AZD8931 is more efficacious than either agent alone, resulting in profound tumour regressions. We conclude that the activity of AZD5363 in HER2-amplified breast cancer cells is enhanced by the addition of AZD8931 and that dual targeting of AKT and EGFR/HER2/HER3 signalling is an attractive treatment option to be explored in the clinic.
authors.affiliation: Oncology iMED, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Crafter
authors.affiliation: Oncology iMED, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK.
authors.forename: John P
authors.initials: JP
authors.lastname: Vincent
authors.affiliation: Oncology iMED, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK.
authors.forename: Eric
authors.initials: E
authors.lastname: Tang
authors.affiliation: Oncology iMED, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK.
authors.forename: Phillippa
authors.initials: P
authors.lastname: Dudley
authors.affiliation: Oncology iMED, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK.
authors.forename: Neil H
authors.initials: NH
authors.lastname: James
authors.affiliation: Oncology iMED, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK.
authors.forename: Teresa
authors.initials: T
authors.lastname: Klinowska
authors.affiliation: Oncology iMED, AstraZeneca, Alderley Park, Macclesfield SK10 4TG, UK.
authors.forename: Barry R
authors.initials: BR
authors.lastname: Davies
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D005260:Female; D005784:Gene Amplification; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011743:Pyrimidines / Q000008:administration & dosage* / Q000494:pharmacology; D011758:Pyrroles / Q000008:administration & dosage* / Q000494:pharmacology; D011799:Quinazolines / Q000008:administration & dosage* / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D051057:Proto-Oncogene Proteins c-akt; D011743:Pyrimidines; D011758:Pyrroles; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; C548875:AZD 8931; C508053:ERBB2 protein, human; C575618:capivasertib