PMID- 37071495
OWN - NLM
STAT- MEDLINE
DCOM- 20231003
LR  - 20240129
IS  - 1538-7445 (Electronic)
IS  - 0008-5472 (Print)
IS  - 0008-5472 (Linking)
VI  - 83
IP  - 19
DP  - 2023 Oct 2
TI  - Kinome Reprogramming Is a Targetable Vulnerability in ESR1 Fusion-Driven Breast 
      Cancer.
PG  - 3237-3251
LID - 10.1158/0008-5472.CAN-22-3484 [doi]
AB  - Transcriptionally active ESR1 fusions (ESR1-TAF) are a potent cause of breast 
      cancer endocrine therapy (ET) resistance. ESR1-TAFs are not directly druggable 
      because the C-terminal estrogen/anti-estrogen-binding domain is replaced with 
      translocated in-frame partner gene sequences that confer constitutive 
      transactivation. To discover alternative treatments, a mass spectrometry 
      (MS)-based kinase inhibitor pulldown assay (KIPA) was deployed to identify 
      druggable kinases that are upregulated by diverse ESR1-TAFs. Subsequent 
      explorations of drug sensitivity validated RET kinase as a common therapeutic 
      vulnerability despite remarkable ESR1-TAF C-terminal sequence and structural 
      diversity. Organoids and xenografts from a pan-ET-resistant patient-derived 
      xenograft model that harbors the ESR1-e6>YAP1 TAF were concordantly inhibited by 
      the selective RET inhibitor pralsetinib to a similar extent as the CDK4/6 
      inhibitor palbociclib. Together, these findings provide preclinical rationale for 
      clinical evaluation of RET inhibition for the treatment of ESR1-TAF-driven 
      ET-resistant breast cancer. SIGNIFICANCE: Kinome analysis of ESR1 translocated 
      and mutated breast tumors using drug bead-based mass spectrometry followed by 
      drug-sensitivity studies nominates RET as a therapeutic target. See related 
      commentary by Wu and Subbiah, p. 3159.
CI  - (c)2023 The Authors; Published by the American Association for Cancer Research.
FAU - Gou, Xuxu
AU  - Gou X
AUID- ORCID: 0000-0003-2318-778X
AD  - Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
AD  - Graduate Program in Translational Biology and Molecular Medicine, Baylor College 
      of Medicine, Houston Texas.
AD  - UCSF Helen Diller Family Comprehensive Cancer Center, University of California 
      San Francisco, San Francisco, California.
FAU - Kim, Beom-Jun
AU  - Kim BJ
AUID- ORCID: 0000-0003-3109-8170
AD  - Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
AD  - Department of Medicine, Baylor College of Medicine, Houston, Texas.
FAU - Anurag, Meenakshi
AU  - Anurag M
AUID- ORCID: 0000-0003-4379-5192
AD  - Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
AD  - Department of Medicine, Baylor College of Medicine, Houston, Texas.
FAU - Lei, Jonathan T
AU  - Lei JT
AUID- ORCID: 0000-0002-0209-8051
AD  - Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
AD  - Department of Human and Molecular Genetics, Baylor College of Medicine, Houston, 
      Texas.
FAU - Young, Meggie N
AU  - Young MN
AUID- ORCID: 0000-0003-2684-7317
AD  - Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
AD  - Department of Biochemistry and Molecular Biology, Baylor College of Medicine, 
      Houston, Texas.
FAU - Holt, Matthew V
AU  - Holt MV
AUID- ORCID: 0000-0002-1418-6139
AD  - Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
FAU - Fandino, Diana
AU  - Fandino D
AUID- ORCID: 0009-0006-3815-8585
AD  - Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
FAU - Vollert, Craig T
AU  - Vollert CT
AUID- ORCID: 0000-0002-3769-0805
AD  - Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
AD  - Employee of Adrienne Helis Malvin Medical Research Foundation, New Orleans, Los 
      Angeles.
FAU - Singh, Purba
AU  - Singh P
AUID- ORCID: 0009-0005-0341-1061
AD  - Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
FAU - Alzubi, Mohammad A
AU  - Alzubi MA
AUID- ORCID: 0000-0002-3953-8436
AD  - Employee of Adrienne Helis Malvin Medical Research Foundation, New Orleans, Los 
      Angeles.
FAU - Malovannaya, Anna
AU  - Malovannaya A
AUID- ORCID: 0000-0003-2953-6485
AD  - Department of Biochemistry and Molecular Biology, Baylor College of Medicine, 
      Houston, Texas.
FAU - Dobrolecki, Lacey E
AU  - Dobrolecki LE
AUID- ORCID: 0000-0001-6839-629X
AD  - Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
FAU - Lewis, Michael T
AU  - Lewis MT
AUID- ORCID: 0000-0002-6330-4007
AD  - Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
AD  - Department of Molecular and Cellular Biology, Baylor College of Medicine, 
      Houston, Texas.
AD  - Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
AD  - Department of Radiology, Baylor College of Medicine, Houston, Texas.
FAU - Li, Shunqiang
AU  - Li S
AUID- ORCID: 0000-0001-9508-7249
AD  - Division of Oncology, Department of Internal Medicine, Washington University 
      School of Medicine, St. Louis, Missouri.
FAU - Foulds, Charles E
AU  - Foulds CE
AUID- ORCID: 0000-0003-4908-1473
AD  - Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
AD  - Department of Medicine, Baylor College of Medicine, Houston, Texas.
AD  - Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
FAU - Ellis, Matthew J
AU  - Ellis MJ
AUID- ORCID: 0000-0002-8467-8534
AD  - Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas.
AD  - Graduate Program in Translational Biology and Molecular Medicine, Baylor College 
      of Medicine, Houston Texas.
AD  - Department of Medicine, Baylor College of Medicine, Houston, Texas.
AD  - Department of Molecular and Cellular Biology, Baylor College of Medicine, 
      Houston, Texas.
AD  - Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, Texas.
LA  - eng
GR  - U54 CA224076/CA/NCI NIH HHS/United States
GR  - U54 CA233223/CA/NCI NIH HHS/United States
GR  - S10 OD026804/OD/NIH HHS/United States
GR  - U54 CA224083/CA/NCI NIH HHS/United States
GR  - P30 CA125123/CA/NCI NIH HHS/United States
GR  - U01 CA214125/CA/NCI NIH HHS/United States
GR  - T32 CA203690/CA/NCI NIH HHS/United States
GR  - P50 CA186784/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PL  - United States
TA  - Cancer Res
JT  - Cancer research
JID - 2984705R
RN  - 0 (Estrogen Receptor alpha)
RN  - 0 (Antineoplastic Agents)
SB  - IM
CIN - Cancer Res. 2023 Oct 2;83(19):3159-3161. PMID: 37779428
MH  - Animals
MH  - Humans
MH  - Female
MH  - *Breast Neoplasms/drug therapy/genetics/pathology
MH  - Estrogen Receptor alpha/genetics
MH  - *Antineoplastic Agents/therapeutic use
MH  - Disease Models, Animal
MH  - Mutation
PMC - PMC10543968
EDAT- 2023/04/19 06:00
MHDA- 2023/10/03 06:47
PMCR- 2023/10/02
CRDT- 2023/04/18 12:12
PHST- 2022/11/04 00:00 [received]
PHST- 2023/02/20 00:00 [revised]
PHST- 2023/04/12 00:00 [accepted]
PHST- 2023/10/03 06:47 [medline]
PHST- 2023/04/19 06:00 [pubmed]
PHST- 2023/04/18 12:12 [entrez]
PHST- 2023/10/02 00:00 [pmc-release]
AID - 725885 [pii]
AID - CAN-22-3484 [pii]
AID - 10.1158/0008-5472.CAN-22-3484 [doi]
PST - ppublish
SO  - Cancer Res. 2023 Oct 2;83(19):3237-3251. doi: 10.1158/0008-5472.CAN-22-3484.