BRAF inhibitor-associated ERK activation drives development of chronic lymphocytic leukemia.
BRAF inhibitor-associated ERK activation drives development of chronic lymphocytic leukemia.
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DOI：
10.1172/jci76539
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发表时间：
2014-11
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通讯作者：
Niuscha Yaktapour;F. Meiss;Justin Mastroianni;T. Zenz;Hana Andrlová;Nimitha R. Mathew;R. Claus;B. Hut
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文献类型：
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作者：
Niuscha Yaktapour;F. Meiss;Justin Mastroianni;T. Zenz;Hana Andrlová;Nimitha R. Mathew;R. Claus;B. Hut
BRAFV 600 E/K驱动的黑色素瘤患者对BRAF抑制剂维罗非尼有反应，因为随后增殖性RAS/RAF/MEK/ERK通路失活。在BRAF WT细胞和具有激活或导致高水平BRAF激活剂RAS的突变的那些细胞中，BRAF抑制可导致ERK激活，从而导致致瘤性转化。我们描述了一例恶性黑色素瘤患者，在维罗非尼治疗期间，在没有RAS突变的情况下发生慢性淋巴细胞白血病（CLL）。BRAF抑制促进培养物和鼠异种移植物中的患者CLL增殖，并活化来自其他患者的原代CLL细胞中的MEK/ERK。BRAF受体驱动的ERK活性和CLL增殖需要B细胞抗原受体（BCR）活化，因为抑制BCR近端脾酪氨酸激酶（SYK）可逆转ERK过度活化和多例患者CLL细胞增殖，而抑制BCR远端布鲁顿酪氨酸激酶则无影响。此外，在SYK抑制后，暴露于维罗非尼的原代CLL细胞中的RAS-GTP/RAS比率降低。BRAF抑制增加了携带CLL异种移植物的小鼠的死亡率和CLL扩增;然而，SYK或MEK抑制阻止了CLL增殖并增加了动物存活率。总之，这些结果表明，BRAF抑制剂在RAS或其他受体酪氨酸激酶没有明显突变的情况下促进B细胞恶性肿瘤，并为BRAF/MEK或BRAF/SYK联合抑制提供了理论依据。
Patients with BRAFV600E/K-driven melanoma respond to the BRAF inhibitor vemurafenib due to subsequent deactivation of the proliferative RAS/RAF/MEK/ERK pathway. In BRAF WT cells and those with mutations that activate or result in high levels of the BRAF activator RAS, BRAF inhibition can lead to ERK activation, resulting in tumorigenic transformation. We describe a patient with malignant melanoma who developed chronic lymphocytic leukemia (CLL) in the absence of RAS mutations during vemurafenib treatment. BRAF inhibition promoted patient CLL proliferation in culture and in murine xenografts and activated MEK/ERK in primary CLL cells from additional patients. BRAF inhibitor-driven ERK activity and CLL proliferation required B cell antigen receptor (BCR) activation, as inhibition of the BCR-proximal spleen tyrosine kinase (SYK) reversed ERK hyperactivation and proliferation of CLL cells from multiple patients, while inhibition of the BCR-distal Bruton tyrosine kinase had no effect. Additionally, the RAS-GTP/RAS ratio in primary CLL cells exposed to vemurafenib was reduced upon SYK inhibition. BRAF inhibition increased mortality and CLL expansion in mice harboring CLL xenografts; however, SYK or MEK inhibition prevented CLL proliferation and increased animal survival. Together, these results suggest that BRAF inhibitors promote B cell malignancies in the absence of obvious mutations in RAS or other receptor tyrosine kinases and provide a rationale for combined BRAF/MEK or BRAF/SYK inhibition.