2. Academic Validation
  3. Growth factor receptor plasticity drives therapeutic persistence of metastatic breast cancer

Growth factor receptor plasticity drives therapeutic persistence of metastatic breast cancer

  • Cell Death Dis. 2025 Apr 4;16(1):251. doi: 10.1038/s41419-025-07591-3.
Mitchell Ayers 1 2,  Marvis Monteiro 1 2,  Aneesha Kulkarni 1 2,  Julie W Reeser 3 4,  Emily Dykhuizen 1 2,  Sameek Roychowdhury 3 4,  Michael K Wendt 5 6 7 8
Affiliations

Affiliations

  • 1 Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, 47907, USA.
  • 2 Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN, 47907, USA.
  • 3 Comprehensive Cancer Center and James Cancer Hospital, The Ohio State University, Columbus, OH, 43210, USA.
  • 4 Department of Internal Medicine, Division of Medical Oncology, The Ohio State University, Columbus, OH, 43210, USA.
  • 5 Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, IN, 47907, USA. mkwendt@uiowa.edu.
  • 6 Purdue Institute for Cancer Research, Purdue University, West Lafayette, IN, 47907, USA. mkwendt@uiowa.edu.
  • 7 Department of Internal Medicine, University of Iowa, Iowa City, IA, 52242, USA. mkwendt@uiowa.edu.
  • 8 Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, 52242, USA. mkwendt@uiowa.edu.
PMID: 40185706 DOI: 10.1038/s41419-025-07591-3
Abstract

Metastatic breast Cancer (MBC) remains a therapeutic challenge due to the persistence of minimal residual disease (MRD) and tumor recurrence. Herein we utilize a model of MBC that is sensitive to inhibition of Fibroblast Growth Factor receptor (FGFR), resulting in robust regression of pulmonary lesions upon treatment with the FGFR Inhibitor pemigatinib. Assessment of the remaining MRD revealed upregulation of platelet-derived growth factor receptor (PDGFR). Functionally, we demonstrate increased response to PDGF ligand stimulation following pemigatinib treatment. Depletion of PDGFR did not alter tumor growth under control conditions but did delay tumor recurrence following a treatment window of pemigatinib. To overcome this therapeutic hurdle, we found that inhibition of DNA Methyltransferase 1 (DNMT1) prevents pemigatinib-induced cellular plasticity. Combined targeting of FGFR and DNMT1 prevented induction of PDGFR, enhanced pulmonary tumor regression, slowed tumor recurrence, and prolonged survival. These findings enhance our understanding of cellular plasticity during states of treatment-induced MRD and suggest that inhibition of DNA methylation could augment current approaches being used to treat MBC.

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