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.
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.
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.
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.
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This study was supported in part by a research grant from AstraZeneca; by Susan G. Komen for the Cure: Promise Grant PG12221410 (to R.S. and C.K.O.); by a grant from the Breast Cancer Research Foundation BCRF-18-145; and by the NIH: SPORE Grants P50CA058183 and CA186784, and Cancer Center Grant P30CA125123.
R.S. has received research funding (to institution) from AstraZeneca, Gilead, PUMA, and GlaxoSmithKline (GSK). She is a consulting/advisory committee member for Macrogenics, and Eli Lilly. C.K.O. has received research funding from AstraZeneca and GSK. He has been a member of advisory boards for Pfizer, Nanostring, Genentech, Tolmar Pharmaceuticals, and AstraZeneca. He is also a member of a DMC for Eli Lilly. M.F.R. has received research funding (to institution) from Pfizer and GSK. He is a consulting member for Genentech, Novartis, Daiichi Sankyo, and Macrogenics. R.J. received research funding from Pfizer. O.D. is an AstraZeneca employee. H.W., M.P., and H.B. are former AstraZeneca employees.
All animal care was in accordance with institutional guidelines.
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Expert Opinion on Pharmacotherapy (2019)
Proceedings of the National Academy of Sciences (2019)
Pharmacokinetic and pharmacodynamic analysis of fulvestrant in preclinical models of breast cancer to assess the importance of its estrogen receptor-α degrader activity in antitumor efficacy
Breast Cancer Research and Treatment (2019)