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
  • 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.

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