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.
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DOI：
10.1186/s12964-023-01400-0
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发表时间：
2023-12-18
影响因子：
8.4
通讯作者：
Liu, Xuejiao
中科院分区：
文献类型：
--
作者：
Guo, Tongxuan;Wu, Changyong;Zhang, Junhao;Yu, Jiefeng;Li, Guoxi;Jiang, Hongyan;Zhang, Xu;Yu, Rutong;Liu, Xuejiao
多形性胶质母细胞瘤（GBM）是一种毁灭性疾病，缺乏有效的靶向治疗药物。此前，我们发现第三代表皮生长因子受体（EGFR）抑制剂AZD-9291持续阻断ERK通路的激活，但对磷酸肌醇3激酶（PI3K）/Akt通路没有抑制作用。鉴于 PI3K 抑制剂 GDC-0084 正在 GBM 治疗的 I/II 期临床试验中进行评估，我们假设联合抑制 EGFR/ERK 和 PI3K/Akt 通路可能在 GBM 治疗中产生协同作用。使用 GBM 和原代 GBM 细胞系中的细胞活力测定验证了 AZD-9291 和 GDC-0084 联合治疗的协同效应。此外，通过集落形成、EdU 增殖和细胞周期测定以及 RNA-seq 分析和蛋白质印迹评估了潜在的抑制机制。使用皮下或颅内注射 LN229 异种移植物，在荷瘤小鼠中研究药物组合对肿瘤生长和存活的治疗效果。与单一疗法相比，AZD-9291 和 GDC-0084 联合治疗可协同抑制增殖和克隆存活，并诱导 GBM 细胞和原代 GBM 细胞的细胞周期停滞。此外，AZD-9291联合GDC-0084联合治疗显着抑制皮下肿瘤和原位脑肿瘤异种移植物的生长，从而延长荷瘤小鼠的生存期。更重要的是，AZD-9291和GDC-0084的组合同时阻断了EGFR/MEK/ERK和PI3K/AKT/mTOR信号通路的激活，从而发挥显着的抗肿瘤活性。我们的研究结果表明，在体外和体内，联合阻断 EGFR/MEK/ERK 和 PI3K/AKT/mTOR 通路比单独抑制每个通路更能有效对抗 GBM。我们的结果表明，AZD-9291 联合 GDC-0084 可被视为未来临床试验中的潜在治疗策略。视频摘要 在线版本包含可在 10.1186/s12964-023-01400-0 获取的补充材料。
Glioblastoma multiforme (GBM) is a devastating disease that lacks effective 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 effect 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 effect in the treatment of GBM. The synergistic effects 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 effects of the drug combination on tumor growth and survival were investigated in mice bearing tumors using subcutaneously or intracranially injected LN229 xenografts. 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 significantly 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 significant antitumor activity. Our findings demonstrate that the combined blockade of the EGFR/MEK/ERK and PI3K/AKT/mTOR pathways is more effective 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. Video Abstract The online version contains supplementary material available at 10.1186/s12964-023-01400-0.
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影响因子：
4.7
作者：
Peng Y;Wang Y;Zhou C;Mei W;Zeng C
通讯作者：
Zeng C
影响因子：
7.5
作者：
Jiang, Jin;Yuan, Zuguo;Fei, Zhenghua
通讯作者：
Fei, Zhenghua
影响因子：
25
作者：
Guo G;Gong K;Ali S;Ali N;Shallwani S;Hatanpaa KJ;Pan E;Mickey B;Burma S;Wang DH;Kesari S;Sarkaria JN;Zhao D;Habib AA
通讯作者：
Habib AA
影响因子：
4.2
作者：
Heffron TP;Ndubaku CO;Salphati L;Alicke B;Cheong J;Drobnick J;Edgar K;Gould SE;Lee LB;Lesnick JD;Lewis C;Nonomiya J;Pang J;Plise EG;Sideris S;Wallin J;Wang L;Zhang X;Olivero AG
通讯作者：
Olivero AG
GDC-0084 抑制皮肤鳞状细胞癌细胞生长
DOI：
10.1016/j.bbrc.2018.07.139
发表时间：
2018-09-10
影响因子：
3.1
作者：
Ding, Ling-tao;Zhao, Peng;Zhao, Tian-lan
通讯作者：
Zhao, Tian-lan