ESR1 (
estrogen receptor 1) hotspot mutations are major contributors to therapeutic resistance in
estrogen receptor-positive (ER+)
breast cancer. Such mutations confer
estrogen independence to ERα, providing a selective advantage in the presence of
estrogen-depleting
aromatase inhibitors. In addition, ESR1 mutations reduce the potency of
tamoxifen and
fulvestrant,
therapies that bind ERα directly. These limitations, together with additional liabilities, inspired the development of the next generation of ERα-targeted
therapeutics, of which
giredestrant is a high-potential candidate. Here, we generated Esr1 mutant-expressing mammary gland models and leveraged patient-derived xenografts (PDXs) to investigate the
biological properties of the ESR1 mutations and their sensitivity to
giredestrant in vivo. In the mouse mammary gland, Esr1 mutations promote
hypersensitivity to
progesterone, triggering pregnancy-like tissue remodeling and profoundly elevated proliferation. These effects were driven by an altered
progesterone transcriptional response and underpinned by gained sites of ERα-PR (
progesterone receptor) cobinding at the promoter regions of pro-proliferation genes. PDX experiments showed that the mutant ERα-PR proliferative program is also relevant in human
cancer cells.
Giredestrant suppressed the mutant ERα-PR proliferation in the mammary gland more so than the standard-of-care agents,
tamoxifen and
fulvestrant.
Giredestrant was also efficacious against the
progesterone-stimulated growth of ESR1 mutant PDX models. In addition,
giredestrant demonstrated activity against a molecularly characterized ESR1 mutant
tumor from a patient enrolled in a phase 1 clinical trial. Together, these data suggest that mutant ERα can collaborate with PR to drive protumorigenic proliferation but remain sensitive to inhibition by
giredestrant.