Efficacy of intermittent combined RAF and MEK inhibition in a patient with concurrent BRAF- and NRAS-mutant malignancies.
Efficacy of intermittent combined RAF and MEK inhibition in a patient with concurrent BRAF- and NRAS-mutant malignancies.
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DOI：
10.1158/2159-8290.cd-13-1038
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发表时间：
2014-05
期刊：
影响因子：
28.2
通讯作者：
Chapman PB
中科院分区：
文献类型：
--
作者：
Abdel-Wahab O;Klimek VM;Gaskell AA;Viale A;Cheng D;Kim E;Rampal R;Bluth M;Harding JJ;Callahan MK;Merghoub T;Berger MF;Solit DB;Rosen N;Levine RL;Chapman PB
维罗非尼是一种RAF抑制剂，可延长BRAFV 600突变型黑色素瘤患者的生存期，但可激活RAS突变型细胞中的细胞外信号调节激酶（ERK）信号。在一例BRAFV 600 K突变型黑色素瘤患者中，我们观察到一种以前未被识别的NRAS突变型白血病的加速进展。我们假设维罗非尼与MAP-ERK激酶（MEK）抑制剂联合使用可抑制黑色素瘤中的ERK激活，并阻止白血病中维罗非尼对ERK的激活，从而抑制两种恶性肿瘤。我们证明，vemurafenib的间歇给药导致黑色素瘤的几乎完全缓解，并且MEK抑制剂cobimetinib（GDC-0973）的加入引起vemurafenib诱导的白血病增殖和ERK激活的抑制。抗黑色素瘤和抗白血病反应已维持近20个月，除了常规的放射学和临床反应评估外，还通过血浆中肿瘤衍生DNA的系列测量记录。这些数据支持在RAS突变型白血病和BRAF突变型黑色素瘤的治疗中间歇性ERK通路抑制的测试。我们发现，在同时患有RAS突变型白血病和BRAF突变型黑色素瘤的患者中，间歇性RAF抑制剂治疗诱导了几乎完全的黑色素瘤反应，并且添加MEK抑制剂防止了RAF抑制剂诱导的RAS突变型白血病的激活。间歇性治疗可以允许更大的通路抑制，具有更小的毒性，避免通路反馈的慢性缓解，并且与慢性给药相比具有增强的有效性。
Vemurafenib, a RAF inhibitor, extends survival in patients with BRAFV600-mutant melanoma but activates extracellular signal–regulated kinase (ERK) signaling in RAS-mutant cells. In a patient with a BRAFV600K-mutant melanoma responding to vemurafenib, we observed accelerated progression of a previously unrecognized NRAS-mutant leukemia. We hypothesized that combining vemurafenib with a MAP–ERK kinase (MEK) inhibitor would inhibit ERK activation in the melanoma and prevent ERK activation by vemurafenib in the leukemia, and thus suppress both malignancies. We demonstrate that intermittent administration of vemurafenib led to a near-complete remission of the melanoma, and the addition of the MEK inhibitor cobimetinib (GDC-0973) caused suppression of vemurafenib-induced leukemic proliferation and ERK activation. Antimelanoma and antileukemia responses have been maintained for nearly 20 months, as documented by serial measurements of tumor-derived DNA in plasma in addition to conventional radiographic and clinical assessments of response. These data support testing of intermittent ERK pathway inhibition in the therapy for both RAS-mutant leukemia and BRAF-mutant melanoma. We show that in a patient with simultaneous RAS-mutant leukemia and BRAF-mutant melanoma, intermittent RAF inhibitor therapy induced a near-complete melanoma response, and addition of a MEK inhibitor prevented RAF inhibitor-induced activation of the RAS-mutant leukemia. Intermittent therapy may permit greater pathway inhibition with less toxicity, avoid chronic relief of pathway feedback, and have enhanced effectiveness compared with chronic administration.