Broad Institute of Massachusetts Institute of Technology, Cambridge, USA.
J Clin Oncol. 2012 Jan 20;30(3):316-21. doi: 10.1200/JCO.2011.36.7680. Epub 2011 Nov 7.
RAF inhibitors are effective against melanomas with BRAF V600E mutations but may induce keratoacanthomas (KAs) and cutaneous squamous cell carcinomas (cSCCs). The potential of these agents to promote secondary malignancies is concerning. We analyzed cSCC and KA lesions for genetic mutations in an attempt to identify an underlying mechanism for their formation.
Four international centers contributed 237 KA or cSCC tumor samples from patients receiving an RAF inhibitor (either vemurafenib or sorafenib; n = 19) or immunosuppression therapy (n = 53) or tumors that developed spontaneously (n = 165). Each sample was profiled for 396 known somatic mutations across 33 cancer-related genes by using a mass spectrometric-based genotyping platform.
Mutations were detected in 16% of tumors (38 of 237), with five tumors harboring two mutations. Mutations in TP53, CDKN2A, HRAS, KRAS, and PIK3CA were previously described in squamous cell tumors. Mutations in MYC, FGFR3, and VHL were identified for the first time. A higher frequency of activating RAS mutations was found in tumors from patients treated with an RAF inhibitor versus populations treated with a non-RAF inhibitor (21.1% v 3.2%; P < .01), although overall mutation rates between treatment groups were similar (RAF inhibitor, 21.1%; immunosuppression, 18.9%; and spontaneous, 17.6%; P = not significant). Tumor histology (KA v cSCC), tumor site (head and neck v other), patient age (≤ 70 v > 70 years), and sex had no significant impact on mutation rate or type.
Squamous cell tumors from patients treated with an RAF inhibitor have a distinct mutational profile that supports a mechanism of therapy-induced tumorigenesis in RAS-primed cells. Conceivably, cotargeting of MEK together with RAF may reduce or prevent formation of these tumors.
RAF 抑制剂对 BRAF V600E 突变的黑色素瘤有效，但可能诱导角化棘皮瘤（KA）和皮肤鳞状细胞癌（cSCC）。这些药物促进继发性恶性肿瘤的潜力令人担忧。我们分析了 cSCC 和 KA 病变中的遗传突变，试图确定其形成的潜在机制。
四个国际中心提供了 19 名接受 RAF 抑制剂（vemurafenib 或 sorafenib）或免疫抑制治疗（n=53）或自发发生的肿瘤（n=165）的患者的 237 例 KA 或 cSCC 肿瘤样本。使用基于质谱的基因分型平台，对每个样本进行了 33 个癌症相关基因中的 396 个已知体细胞突变的分析。
在 16%的肿瘤（237 例中的 38 例）中检测到突变，其中 5 例肿瘤携带两个突变。TP53、CDKN2A、HRAS、KRAS 和 PIK3CA 的突变在鳞状细胞肿瘤中已有描述。首次发现 MYC、FGFR3 和 VHL 的突变。与接受非 RAF 抑制剂治疗的人群相比，接受 RAF 抑制剂治疗的患者的肿瘤中发现了更高频率的激活 RAS 突变（21.1%对 3.2%；P<0.01），尽管治疗组之间的总体突变率相似（RAF 抑制剂组为 21.1%；免疫抑制组为 18.9%；自发组为 17.6%；P=无显著性差异）。肿瘤组织学（KA 对 cSCC）、肿瘤部位（头颈部对其他部位）、患者年龄（≤70 岁对>70 岁）和性别对突变率或类型无显著影响。
接受 RAF 抑制剂治疗的患者的鳞状细胞肿瘤具有独特的突变谱，支持 RAS 启动细胞的治疗诱导肿瘤发生机制。可以想象，MEK 与 RAF 的共同靶向可能会减少或预防这些肿瘤的形成。
