2. Academic Validation
  3. Kinome reprogramming is a targetable vulnerability in ESR1 fusion-driven breast cancer

Kinome reprogramming is a targetable vulnerability in ESR1 fusion-driven breast cancer

  • Cancer Res. 2023 Apr 18;CAN-22-3484. doi: 10.1158/0008-5472.CAN-22-3484.
Xuxu Gou 1,  Beom-Jun Kim 1,  Meenakshi Anurag 2,  Jonathan T Lei 2,  Meggie N Young 2,  Matthew V Holt 2,  Diana Fandino 1,  Craig T Vollert 3,  Purba Singh 4,  Mohammad A Alzubi 5,  Anna Malovannaya 2,  Lacey E Dobrolecki 2,  Michael T Lewis 2,  Shunqiang Li 6,  Charles E Foulds 2,  Matthew J Ellis 2
Affiliations

Affiliations

  • 1 Baylor College of Medicine, Houston, United States.
  • 2 Baylor College of Medicine, Houston, TX, United States.
  • 3 Adrienne Helis Malvin Medical Research Foundation, New Orleans, Louisiana, United States.
  • 4 University of Mississippi Medical Center, United States.
  • 5 Employee of Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA., New Orleans, United States.
  • 6 Washington University in St. Louis, St Louis, MO, United States.
PMID: 37071495 DOI: 10.1158/0008-5472.CAN-22-3484
Abstract

Transcriptionally active ESR1 gene 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 (PDX) 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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-50767
    99.94%, CDK4/6抑制剂
    CDK
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