Journal article
FGFR signaling maintains a drug persistent cell population following epithelial-mesenchymal transition
Oncotarget, Vol.7(50), pp.83424-83436
12/13/2016
DOI: 10.18632/oncotarget.13117
PMCID: PMC5347779
PMID: 27825137
Abstract
An emerging characteristic of drug resistance in cancer is the induction of epithelial-mesenchymal transition (EMT). However, the mechanisms of EMT-mediated drug resistance remain poorly defined. Therefore, we conducted long-term treatments of human epidermal growth factor receptor-2 (Her2)-transformed breast cancer cells with either the EGFR/Her2 kinase inhibitor, Lapatinib or TGF-beta, a known physiological inducer of EMT. Both of these treatment regimes resulted in robust EMT phenotypes, but upon withdrawal a subpopulation of TGF-beta induced cells readily underwent mesenchymal-epithelial transition, where as Lapatinib-induced cells failed to reestablish an epithelial population. The mesenchymal population that remained following TGF-beta stimulation and withdrawal was quickly selected for during subsequent Lapatinib treatment, manifesting in inherent drug resistance. The Nanostring cancer progression gene panel revealed a dramatic upregulation of fibroblast growth factor receptor 1 (FGFR1) and its cognate ligand FGF2 in both acquired and inherent resistance. Mechanistically, FGF: Erk1/2 signaling functions to stabilize the EMT transcription factor Twist and thus maintain the mesenchymal and drug resistant phenotype. Finally, Lapatinib resistant cells could be readily eliminated using recently characterized covalent inhibitors of FGFR. Overall our data demonstrate that next-generation targeting of FGFR can be used in combination with Her2-targeted therapies to overcome resistance in this breast cancer subtype.
Details
- Title: Subtitle
- FGFR signaling maintains a drug persistent cell population following epithelial-mesenchymal transition
- Creators
- Wells S. Brown - Purdue University West LafayetteSaeed Salehin Akhand - Purdue University West LafayetteMichael K. Wendt - Purdue University West Lafayette
- Resource Type
- Journal article
- Publication Details
- Oncotarget, Vol.7(50), pp.83424-83436
- DOI
- 10.18632/oncotarget.13117
- PMID
- 27825137
- PMCID
- PMC5347779
- NLM abbreviation
- Oncotarget
- ISSN
- 1949-2553
- eISSN
- 1949-2553
- Publisher
- Impact Journals LLC
- Number of pages
- 13
- Grant note
- METAvivor foundation P30CA023168 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) R00 CA166140 / National Institutes of Health; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA
- Language
- English
- Date published
- 12/13/2016
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984459628802771
Metrics
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