EGFRvIII Confers Sensitivity to Saracatinib in a STAT5-Dependent Manner in Glioblastoma.
Document Type
Article
Abstract
Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, with few effective treatments. EGFR alterations, including expression of the truncated variant EGFRvIII, are among the most frequent genomic changes in these tumors. EGFRvIII is known to preferentially signal through STAT5 for oncogenic activation in GBM, yet targeting EGFRvIII has yielded limited clinical success to date. In this study, we employed patient-derived xenograft (PDX) models expressing EGFRvIII to determine the key points of therapeutic vulnerability within the EGFRvIII-STAT5 signaling axis in GBM. Our findings reveal that exogenous expression of paralogs STAT5A and STAT5B augments cell proliferation and that inhibition of STAT5 phosphorylation in vivo improves overall survival in combination with temozolomide (TMZ). STAT5 phosphorylation is independent of JAK1 and JAK2 signaling, instead requiring Src family kinase (SFK) activity. Saracatinib, an SFK inhibitor, attenuates phosphorylation of STAT5 and preferentially sensitizes EGFRvIII+ GBM cells to undergo apoptotic cell death relative to wild-type EGFR. Constitutively active STAT5A or STAT5B mitigates saracatinib sensitivity in EGFRvIII+ cells. In vivo, saracatinib treatment decreased survival in mice bearing EGFR WT tumors compared to the control, yet in EGFRvIII+ tumors, treatment with saracatinib in combination with TMZ preferentially improves survival.
Keywords
STAT5 Transcription Factor, Glioblastoma, Humans, Animals, Quinazolines, Benzodioxoles, Mice, ErbB Receptors, Phosphorylation, Cell Line, Tumor, Temozolomide, Cell Proliferation, Xenograft Model Antitumor Assays, Signal Transduction, Brain Neoplasms, Apoptosis, src-Family Kinases, Tumor Suppressor Proteins
Medical Subject Headings
STAT5 Transcription Factor; Glioblastoma; Humans; Animals; Quinazolines; Benzodioxoles; Mice; ErbB Receptors; Phosphorylation; Cell Line, Tumor; Temozolomide; Cell Proliferation; Xenograft Model Antitumor Assays; Signal Transduction; Brain Neoplasms; Apoptosis; src-Family Kinases; Tumor Suppressor Proteins
Publication Date
6-6-2024
Publication Title
Int J Mol Sci
ISSN
1422-0067
Volume
25
Issue
11
PubMed ID
38892466
Digital Object Identifier (DOI)
10.3390/ijms25116279
Recommended Citation
Blomquist, Mylan R; Eghlimi, Ryan; Beniwal, Angad; Grief, Dustin; Nascari, David G; Inge, Landon; Sereduk, Christopher P; Tuncali, Serdar; Roos, Alison; Inforzato, Hannah; Sharma, Ritin; Pirrotte, Patrick; Mehta, Shwetal; Fortin Ensign, Shannon P; Loftus, Joseph C; and Tran, Nhan L, "EGFRvIII Confers Sensitivity to Saracatinib in a STAT5-Dependent Manner in Glioblastoma." (2024). Translational Neuroscience. 2390.
https://scholar.barrowneuro.org/neurobiology/2390