The oral selective oestrogen receptor degrader (SERD) AZD9496 is comparable to fulvestrant in antagonising ER and circumventing endocrine resistance.
Cataldo, Maria Letizia
Shea, Martin J
Rimawi, Mothaffar F
Hilsenbeck, Susan G
Chamness, Gary C
Osborne, C Kent
British journal of cancer
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Nardone, A., Weir, H., Delpuech, O., Brown, H., De Angelis, C., Cataldo, M. L., Fu, X., et al. (2019). The oral selective oestrogen receptor degrader (SERD) AZD9496 is comparable to fulvestrant in antagonising ER and circumventing endocrine resistance.. British journal of cancer, 120 (3), 331-339. https://doi.org/10.1038/s41416-018-0354-9
BACKGROUND: The oestrogen receptor (ER) is an important therapeutic target in ER-positive (ER+) breast cancer. The selective ER degrader (SERD), fulvestrant, is effective in patients with metastatic breast cancer, but its intramuscular route of administration and low bioavailability are major clinical limitations. METHODS: Here, we studied the pharmacology of a new oral SERD, AZD9496, in a panel of in vitro and in vivo endocrine-sensitive and -resistant breast cancer models. RESULTS: In endocrine-sensitive models, AZD9496 inhibited cell growth and blocked ER activity in the presence or absence of oestrogen. In vivo, in the presence of oestrogen, short-term AZD9496 treatment, like fulvestrant, resulted in tumour growth inhibition and reduced expression of ER-dependent genes. AZD9496 inhibited cell growth in oestrogen deprivation-resistant and tamoxifen-resistant cell lines and xenograft models that retain ER expression. AZD9496 effectively reduced ER levels and ER-induced transcription. Expression analysis of short-term treated tumours showed that AZD9496 potently inhibited classic oestrogen-induced gene transcription, while simultaneously increasing expression of genes negatively regulated by ER, including genes potentially involved in escape pathways of endocrine resistance. CONCLUSIONS: These data suggest that AZD9496 is a potent anti-oestrogen that antagonises and degrades ER with anti-tumour activity in both endocrine-sensitive and endocrine-resistant models.
Animals, Humans, Mice, Breast Neoplasms, Neoplasms, Hormone-Dependent, Cinnamates, Tamoxifen, Indoles, Estradiol, Receptors, Estrogen, Estrogens, Cell Proliferation, Drug Resistance, Neoplasm, Female, MCF-7 Cells, Heterografts, Fulvestrant
External DOI: https://doi.org/10.1038/s41416-018-0354-9
This record's URL: https://www.repository.cam.ac.uk/handle/1810/300281
Attribution 4.0 International (CC BY)
Licence URL: http://creativecommons.org/licenses/by/4.0/