Growth factor receptor plasticity drives therapeutic persistence of metastatic breast cancer
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 pulmo...
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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-04-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-025-07591-3 |
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| author | Mitchell Ayers Marvis Monteiro Aneesha Kulkarni Julie W. Reeser Emily Dykhuizen Sameek Roychowdhury Michael K. Wendt |
| author_facet | Mitchell Ayers Marvis Monteiro Aneesha Kulkarni Julie W. Reeser Emily Dykhuizen Sameek Roychowdhury Michael K. Wendt |
| author_sort | Mitchell Ayers |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e0391edd3b8d4924a2d75d19fec88a35 |
| institution | OA Journals |
| issn | 2041-4889 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj-art-e0391edd3b8d4924a2d75d19fec88a352025-08-20T01:54:25ZengNature Publishing GroupCell Death and Disease2041-48892025-04-0116111210.1038/s41419-025-07591-3Growth factor receptor plasticity drives therapeutic persistence of metastatic breast cancerMitchell Ayers0Marvis Monteiro1Aneesha Kulkarni2Julie W. Reeser3Emily Dykhuizen4Sameek Roychowdhury5Michael K. Wendt6Department of Medicinal Chemistry and Molecular Pharmacology, Purdue UniversityDepartment of Medicinal Chemistry and Molecular Pharmacology, Purdue UniversityDepartment of Medicinal Chemistry and Molecular Pharmacology, Purdue UniversityComprehensive Cancer Center and James Cancer Hospital, The Ohio State UniversityDepartment of Medicinal Chemistry and Molecular Pharmacology, Purdue UniversityComprehensive Cancer Center and James Cancer Hospital, The Ohio State UniversityDepartment of Medicinal Chemistry and Molecular Pharmacology, Purdue UniversityAbstract 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.https://doi.org/10.1038/s41419-025-07591-3 |
| spellingShingle | Mitchell Ayers Marvis Monteiro Aneesha Kulkarni Julie W. Reeser Emily Dykhuizen Sameek Roychowdhury Michael K. Wendt Growth factor receptor plasticity drives therapeutic persistence of metastatic breast cancer Cell Death and Disease |
| title | Growth factor receptor plasticity drives therapeutic persistence of metastatic breast cancer |
| title_full | Growth factor receptor plasticity drives therapeutic persistence of metastatic breast cancer |
| title_fullStr | Growth factor receptor plasticity drives therapeutic persistence of metastatic breast cancer |
| title_full_unstemmed | Growth factor receptor plasticity drives therapeutic persistence of metastatic breast cancer |
| title_short | Growth factor receptor plasticity drives therapeutic persistence of metastatic breast cancer |
| title_sort | growth factor receptor plasticity drives therapeutic persistence of metastatic breast cancer |
| url | https://doi.org/10.1038/s41419-025-07591-3 |
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