Growth factor receptor plasticity drives therapeutic persistence of metastatic breast cancer

Mitchell Ayers; Marvis Monteiro; Aneesha Kulkarni; Julie W. Reeser; Emily Dykhuizen; Sameek Roychowdhury; Michael K. Wendt

doi:10.1038/s41419-025-07591-3

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Growth factor receptor plasticity drives therapeutic persistence of metastatic breast cancer

Journal article

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Peer reviewed

Growth factor receptor plasticity drives therapeutic persistence of metastatic breast cancer

Mitchell Ayers, Marvis Monteiro, Aneesha Kulkarni, Julie W. Reeser, Emily Dykhuizen, Sameek Roychowdhury and Michael K. Wendt

Cell death & disease, Vol.16(1), 251

12/01/2025

DOI: 10.1038/s41419-025-07591-3

PMCID: PMC11971261

PMID: 40185706

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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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Title: Subtitle: Growth factor receptor plasticity drives therapeutic persistence of metastatic breast cancer
Creators: Mitchell Ayers - Purdue University Institute for Cancer Research
Marvis Monteiro - Purdue University Institute for Cancer Research
Aneesha Kulkarni - Purdue University Institute for Cancer Research
Julie W. Reeser - The Ohio State University
Emily Dykhuizen - Purdue University Institute for Cancer Research
Sameek Roychowdhury - The Ohio State University
Michael K. Wendt - University of Iowa
Resource Type: Journal article
Publication Details: Cell death & disease, Vol.16(1), 251
DOI: 10.1038/s41419-025-07591-3
PMID: 40185706
PMCID: PMC11971261
NLM abbreviation: Cell Death Dis
ISSN: 2041-4889
eISSN: 2041-4889
Publisher: Nature Publishing Group UK
Grant note: R01CA271597; R01CA281216; P30CA086862; P30CA023168; UH3CA262220 / U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) (https://doi.org/10.13039/100000054)
Language: English
Date published: 12/01/2025
Academic Unit: Holden Comprehensive Cancer Center; Internal Medicine
Record Identifier: 9984804806402771

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