Journal article
Biased signaling downstream of epidermal growth factor receptor regulates proliferative versus apoptotic response to ligand
Cell death & disease, Vol.9(10), pp.976-12
09/24/2018
DOI: 10.1038/s41419-018-1034-7
PMCID: 6155319
PMID: 30250119
Abstract
Inhibition of epidermal growth factor receptor (EGFR) signaling by small molecule kinase inhibitors and monoclonal antibodies has proven effective in the treatment of multiple cancers. In contrast, metastatic breast cancers (BC) derived from EGFR-expressing mammary tumors are inherently resistant to EGFR-targeted therapies. Mechanisms that contribute to this inherent resistance remain poorly defined. Here, we show that in contrast to primary tumors, ligand-mediated activation of EGFR in metastatic BC is dominated by STAT1 signaling. This change in downstream signaling leads to apoptosis and growth inhibition in response to epidermal growth factor (EGF) in metastatic BC cells. Mechanistically, these changes in downstream signaling result from an increase in the internalized pool of EGFR in metastatic cells, increasing physical access to the nuclear pool of STAT1. Along these lines, an EGFR mutant that is defective in endocytosis is unable to elicit STAT1 phosphorylation and apoptosis. Additionally, inhibition of endosomal signaling using an EGFR inhibitor linked to a nuclear localization signal specifically prevents EGF-induced STAT1 phosphorylation and cell death, without affecting EGFR:ERK1/2 signaling. Pharmacologic blockade of ERK1/2 signaling through the use of the allosteric MEK1/2 inhibitor, trametinib, dramatically biases downstream EGFR signaling toward a STAT1-dominated event, resulting in enhanced EGF-induced apoptosis in metastatic BC cells. Importantly, combined administration of trametinib and EGF also facilitated an apoptotic switch in EGFR-transformed primary tumor cells, but not normal mammary epithelial cells. These studies reveal a fundamental distinction for EGFR function in metastatic BC. Furthermore, the data demonstrate that pharmacological biasing of EGFR signaling toward STAT1 activation is capable of revealing the apoptotic function of this critical pathway.
Details
- Title: Subtitle
- Biased signaling downstream of epidermal growth factor receptor regulates proliferative versus apoptotic response to ligand
- Creators
- Remah Ali - Purdue University West LafayetteWells Brown - Purdue University West LafayetteStephen Connor Purdy - Purdue University West LafayetteV. Jo Davisson - Purdue University West LafayetteMichael K. Wendt - Purdue University West Lafayette
- Resource Type
- Journal article
- Publication Details
- Cell death & disease, Vol.9(10), pp.976-12
- DOI
- 10.1038/s41419-018-1034-7
- PMID
- 30250119
- PMCID
- 6155319
- NLM abbreviation
- Cell Death Dis
- ISSN
- 2041-4889
- eISSN
- 2041-4889
- Publisher
- Nature Publishing Group UK
- Grant note
- RSG-CSM130259 / ; R01CA207751 / ;
- Language
- English
- Date published
- 09/24/2018
- Academic Unit
- Internal Medicine
- Record Identifier
- 9984459635502771
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