Autophagy inhibition overcomes multiple mechanisms of resistance to BRAF inhibition in brain tumors
Autophagy inhibition overcomes multiple mechanisms of resistance to BRAF inhibition in brain tumors
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DOI：
10.7554/elife.19671
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发表时间：
2017-01-17
期刊：
影响因子：
7.7
通讯作者：
Thorburn, Andrew
中科院分区：
文献类型：
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作者：
Levy, Jean M. Mulcahy;Zahedi, Shadi;Thorburn, Andrew
激酶抑制剂是有效的癌症疗法，但肿瘤经常产生耐药性。目前规避耐药性的策略针对相同或平行的途径。我们在这里报告说，靶向一个完全不同的过程，自噬，可以克服脑肿瘤中的多种BRAF抑制剂耐药机制。BRAF（V600E）突变发生在许多儿科脑肿瘤中。我们先前报道这些肿瘤是自噬依赖性的，并且在BRAF（V600E）抑制剂维罗非尼失败后，患者成功地用自噬抑制剂氯喹治疗，这表明自噬抑制克服了激酶抑制剂抗性。我们在维罗非尼耐药的脑肿瘤中测试了这一假设。遗传和药理学自噬抑制克服了分子上不同的耐药机制，抑制肿瘤细胞生长并增加细胞死亡。当氯喹加入维罗非尼时，耐药患者有良好的临床反应。这提供了一种根本不同的策略来规避激酶抑制剂耐药的多种机制，可以在BRAF（V600E）脑肿瘤患者的临床试验中快速进行测试。
Kinase inhibitors are effective cancer therapies, but tumors frequently develop resistance. Current strategies to circumvent resistance target the same or parallel pathways. We report here that targeting a completely different process, autophagy, can overcome multiple BRAF inhibitor resistance mechanisms in brain tumors. BRAF(V600E)mutations occur in many pediatric brain tumors. We previously reported that these tumors are autophagy-dependent and a patient was successfully treated with the autophagy inhibitor chloroquine after failure of the BRAF(V600E) inhibitor vemurafenib, suggesting autophagy inhibition overcame the kinase inhibitor resistance. We tested this hypothesis in vemurafenib-resistant brain tumors. Genetic and pharmacological autophagy inhibition overcame molecularly distinct resistance mechanisms, inhibited tumor cell growth, and increased cell death. Patients with resistance had favorable clinical responses when chloroquine was added to vemurafenib. This provides a fundamentally different strategy to circumvent multiple mechanisms of kinase inhibitor resistance that could be rapidly tested in clinical trials in patients with BRAF(V600E) brain tumors.