Concurrent MEK targeted therapy prevents MAPK pathway reactivation during BRAFV600E targeted inhibition in a novel syngeneic murine glioma model
Concurrent MEK targeted therapy prevents MAPK pathway reactivation during BRAFV600E targeted inhibition in a novel syngeneic murine glioma model
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DOI：
10.18632/oncotarget.12419
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发表时间：
2016-11-15
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影响因子：
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通讯作者：
Petritsch, Claudia K.
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文献类型：
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作者：
Grossauer, Stefan;Koeck, Katharina;Petritsch, Claudia K.
BRAF（V600 E）激酶抑制剂目前正在涉及BRAF（V600 E）胶质瘤的临床前和临床研究中进行研究。研究表明，在大多数患者中对这种个体化治疗有临床反应，而在一些患者中，尽管进行了治疗，肿瘤仍继续生长。为了研究耐药机制，包括黑色素瘤中丝裂原活化蛋白激酶（MAPK）信号传导的反馈激活，我们从BRAF（V600 E）突变体和Cdkn 2a缺陷型小鼠高级别胶质瘤中开发了一种经酶修饰的细胞系（2341（luc）），并分析了其对BRAF（V600 E）和MAPK激酶（MEK）靶向抑制的分子反应。对颅内移植了2341（luc）的免疫活性同系FVB/N小鼠进行了BRAF（V600 E）和MEK抑制剂治疗效果的检测，治疗开始后长达14天的生物发光成像和生存分析作为抑制剂活性的主要指标。颅内注射的肿瘤细胞在同基因小鼠中持续产生高级别胶质瘤样肿瘤。每日腹膜内递送BRAF（V600 E）抑制剂达拉非尼仅短暂抑制MAPK信号传导，而是增加Akt信号传导，并且未能延长患有颅内2341（luc）肿瘤的小鼠的存活。MEK抑制剂曲美替尼每日经口灌胃给药可更有效地抑制MAPK通路，并且具有比达拉非尼更持久的抗生长作用以及显著的生存益处。与单独的任一药剂相比，BRAF（V600 E）和MEK抑制剂组合治疗在减少肿瘤生长和延长动物受试者存活方面更有效，这对应于持续的MAPK途径抑制。来自2341（luc）移植模型应用的结果对BRAF（V600 E）胶质瘤的管理具有临床意义。
Inhibitors of BRAF(V600E) kinase are currently under investigations in preclinical and clinical studies involving BRAF(V600E) glioma. Studies demonstrated clinical response to such individualized therapy in the majority of patients whereas in some patients tumors continue to grow despite treatment. To study resistance mechanisms, which include feedback activation of mitogen-activated protein kinase (MAPK) signaling in melanoma, we developed a luciferase-modified cell line (2341(luc)) from a BRAF(V600E) mutant and Cdkn2a- deficient murine high-grade glioma, and analyzed its molecular responses to BRAF(V600E)- and MAPK kinase (MEK)-targeted inhibition. Immunocompetent, syngeneic FVB/N mice with intracranial grafts of 2341(luc) were tested for effects of BRAF(V600E) and MEK inhibitor treatments, with bioluminescence imaging up to 14-days after start of treatment and survival analysis as primary indicators of inhibitor activity. Intracranial injected tumor cells consistently generated high-grade glioma-like tumors in syngeneic mice. Intraperitoneal daily delivery of BRAF(V600E) inhibitor dabrafenib only transiently suppressed MAPK signaling, and rather increased Akt signaling and failed to extend survival for mice with intracranial 2341(luc) tumor. MEK inhibitor trametinib delivered by oral gavage daily suppressed MAPK pathway more effectively and had a more durable anti-growth effect than dabrafenib as well as a significant survival benefit. Compared with either agent alone, combined BRAF(V600E) and MEK inhibitor treatment was more effective in reducing tumor growth and extending animal subject survival, as corresponding to sustained MAPK pathway inhibition. Results derived from the 2341(luc) engraftment model application have clinical implications for the management of BRAF(V600E) glioma.