PMID- 36130016
OWN - NLM
STAT- MEDLINE
DCOM- 20220923
LR  - 20221222
IS  - 1946-6242 (Electronic)
IS  - 1946-6234 (Linking)
VI  - 14
IP  - 663
DP  - 2022 Sep 21
TI  - Giredestrant reverses progesterone hypersensitivity driven by estrogen receptor 
      mutations in breast cancer.
PG  - eabo5959
LID - 10.1126/scitranslmed.abo5959 [doi]
AB  - 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 ERalpha, 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 
      ERalpha directly. These limitations, together with additional liabilities, inspired 
      the development of the next generation of ERalpha-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 
      ERalpha-PR (progesterone receptor) cobinding at the promoter regions of 
      pro-proliferation genes. PDX experiments showed that the mutant ERalpha-PR 
      proliferative program is also relevant in human cancer cells. Giredestrant 
      suppressed the mutant ERalpha-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 ERalpha can collaborate with PR to 
      drive protumorigenic proliferation but remain sensitive to inhibition by 
      giredestrant.
FAU - Liang, Jackson
AU  - Liang J
AUID- ORCID: 0000-0003-3778-4614
AD  - Department of Discovery Oncology, Genentech, South San Francisco, CA 94080, USA.
FAU - Ingalla, Ellen Rei
AU  - Ingalla ER
AUID- ORCID: 0000-0002-3262-3582
AD  - Translational Oncology, Genentech, South San Francisco, CA 94080, USA.
FAU - Yao, Xiaosai
AU  - Yao X
AUID- ORCID: 0000-0001-9729-0726
AD  - Oncology Bioinformatics, Genentech, South San Francisco, CA 94080, USA.
FAU - Wang, Bu-Er
AU  - Wang BE
AUID- ORCID: 0000-0001-7265-6082
AD  - Department of Discovery Oncology, Genentech, South San Francisco, CA 94080, USA.
FAU - Tai, Lisa
AU  - Tai L
AUID- ORCID: 0000-0002-4449-3762
AD  - Research Pathology, Genentech, South San Francisco, CA 94080, USA.
FAU - Giltnane, Jennifer
AU  - Giltnane J
AUID- ORCID: 0000-0002-8333-9995
AD  - Research Pathology, Genentech, South San Francisco, CA 94080, USA.
FAU - Liang, Yuxin
AU  - Liang Y
AUID- ORCID: 0000-0002-1143-423X
AD  - Microchemistry, Proteomics, Lipidomics and Next Generation Sequencing, Genentech, 
      South San Francisco, CA 94080, USA.
FAU - Daemen, Anneleen
AU  - Daemen A
AUID- ORCID: 0000-0001-6287-7105
AD  - Oncology Bioinformatics, Genentech, South San Francisco, CA 94080, USA.
FAU - Moore, Heather M
AU  - Moore HM
AUID- ORCID: 0000-0002-7098-3888
AD  - Oncology Biomarker Development, Genentech, South San Francisco, CA 94080, USA.
FAU - Aimi, Junko
AU  - Aimi J
AD  - Oncology Biomarker Development, Genentech, South San Francisco, CA 94080, USA.
FAU - Chang, Ching-Wei
AU  - Chang CW
AUID- ORCID: 0000-0001-9239-4403
AD  - Biostatistics, Genentech, South San Francisco, CA 94080, USA.
FAU - Gates, Mary R
AU  - Gates MR
AD  - Early Clinical Development, Genentech, South San Francisco, CA 94080, USA.
FAU - Eng-Wong, Jennifer
AU  - Eng-Wong J
AD  - Early Clinical Development, Genentech, South San Francisco, CA 94080, USA.
FAU - Tam, Lucinda
AU  - Tam L
AUID- ORCID: 0000-0002-3101-6684
AD  - Molecular Biology, Genentech, South San Francisco, CA 94080, USA.
FAU - Bacarro, Natasha
AU  - Bacarro N
AUID- ORCID: 0000-0001-6070-6134
AD  - Molecular Biology, Genentech, South San Francisco, CA 94080, USA.
FAU - Roose-Girma, Merone
AU  - Roose-Girma M
AUID- ORCID: 0000-0003-1601-571X
AD  - Molecular Biology, Genentech, South San Francisco, CA 94080, USA.
FAU - Bellet, Meritxell
AU  - Bellet M
AUID- ORCID: 0000-0001-8859-8307
AD  - Department of Medical Oncology, Vall d'Hebron University Hospital and Vall 
      d'Hebron Institute of Oncology (VHIO), Barcelona 08035, Spain.
FAU - Hafner, Marc
AU  - Hafner M
AUID- ORCID: 0000-0003-1337-7598
AD  - Oncology Bioinformatics, Genentech, South San Francisco, CA 94080, USA.
FAU - Metcalfe, Ciara
AU  - Metcalfe C
AUID- ORCID: 0000-0001-7233-661X
AD  - Department of Discovery Oncology, Genentech, South San Francisco, CA 94080, USA.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20220921
PL  - United States
TA  - Sci Transl Med
JT  - Science translational medicine
JID - 101505086
RN  - 0 (Aromatase Inhibitors)
RN  - 0 (Carbolines)
RN  - 0 (Estrogen Receptor alpha)
RN  - 0 (Estrogens)
RN  - 0 (Receptors, Estrogen)
RN  - 0 (Receptors, Progesterone)
RN  - 094ZI81Y45 (Tamoxifen)
RN  - 22X328QOC4 (Fulvestrant)
RN  - 28P3DU6DB3 (giredestrant)
RN  - 4G7DS2Q64Y (Progesterone)
SB  - IM
MH  - Animals
MH  - Aromatase Inhibitors/therapeutic use
MH  - *Breast Neoplasms/drug therapy/genetics/pathology
MH  - Carbolines
MH  - *Estrogen Receptor alpha/genetics/metabolism
MH  - Estrogens
MH  - Female
MH  - Fulvestrant/pharmacology/therapeutic use
MH  - Humans
MH  - Mice
MH  - Mutation/genetics
MH  - Progesterone/pharmacology
MH  - Receptors, Estrogen/genetics
MH  - Receptors, Progesterone/genetics/therapeutic use
MH  - Tamoxifen/pharmacology/therapeutic use
EDAT- 2022/09/22 06:00
MHDA- 2022/09/24 06:00
CRDT- 2022/09/21 14:03
PHST- 2022/09/21 14:03 [entrez]
PHST- 2022/09/22 06:00 [pubmed]
PHST- 2022/09/24 06:00 [medline]
AID - 10.1126/scitranslmed.abo5959 [doi]
PST - ppublish
SO  - Sci Transl Med. 2022 Sep 21;14(663):eabo5959. doi: 10.1126/scitranslmed.abo5959. 
      Epub 2022 Sep 21.