Products Cited in Publications Worldwide Dual blockade of EGFR and PI3K signaling pathways offers a therapeutic strategy for glioblastoma

Dual blockade of EGFR and PI3K signaling pathways offers a therapeutic strategy for glioblastoma

Guo, Tongxuan; Wu, Changyong; Zhang, Junhao; Yu, Jiefeng; Li, Guoxi; Jiang, Hongyan; Zhang, Xu; Yu, Rutong; Liu, Xuejiao

DOI: PMID:

Abstract

Background: Glioblastoma multiforme (GBM) is a devastating disease that lacks efective drugs for targeted therapy. Previously, we found that the third-generation epidermal growth factor receptor (EGFR) inhibitor AZD-9291 persistently blocked the activation of the ERK pathway but had no inhibitory efect on the phosphoinositide 3-kinase (PI3K)/Akt pathway. Given that the PI3K inhibitor GDC-0084 is being evaluated in phase I/II clinical trials of GBM treatment, we hypothesized that combined inhibition of the EGFR/ERK and PI3K/Akt pathways may have a synergistic efect in the treatment of GBM. Methods: The synergistic efects of cotreatment with AZD-9291 and GDC-0084 were validated using cell viability assays in GBM and primary GBM cell lines. Moreover, the underlying inhibitory mechanisms were assessed through colony formation, EdU proliferation, and cell cycle assays, as well as RNA-seq analyses and western blot. The therapeutic efects of the drug combination on tumor growth and survival were investigated in mice bearing tumors using subcutaneously or intracranially injected LN229 xenografts. Results: Combined treatment with AZD-9291 and GDC-0084 synergistically inhibited the proliferation and clonogenic survival, as well as induced cell cycle arrest of GBM cells and primary GBM cells, compared to monotherapy. Moreover, AZD-9291 plus GDC-0084 combination therapy signifcantly inhibited the growth of subcutaneous tumors and orthotopic brain tumor xenografts, thus prolonging the survival of tumor-bearing mice. More importantly, the combination of AZD-9291 and GDC-0084 simultaneously blocked the activation of the EGFR/MEK/ERK and PI3K/AKT/mTOR signaling pathways, thereby exerting signifcant antitumor activity. Conclusion: Our fndings demonstrate that the combined blockade of the EGFR/MEK/ERK and PI3K/AKT/mTOR pathways is more efective against GBM than inhibition of each pathway alone, both in vitro and in vivo. Our results suggest that AZD-9291 combined with GDC-0084 may be considered as a potential treatment strategy in future clinical trials.

Keywords

Glioblastoma ; AZD-9291 ; GDC-0084 ; Combination therapy ; Synergistic inhibition

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Osimertinib

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Osimertinib

10.0/1mg

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GDC-0084

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GDC-0084

14.0/1mg

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