Vanderbilt-Ingram Cancer Center, Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.
Cancer Discov. 2012 Sep;2(9):791-7. doi: 10.1158/2159-8290.CD-12-0097. Epub 2012 Jul 13.
Kinase inhibitors are accepted treatment for metastatic melanomas that harbor specific driver mutations in BRAF or KIT, but only 40% to 50% of cases are positive. To uncover other potential targetable mutations, we conducted whole-genome sequencing of a highly aggressive BRAF (V600) and KIT (W557, V559, L576, K642, and D816) wild-type melanoma. Surprisingly, we found a somatic BRAF(L597R) mutation in exon 15. Analysis of BRAF exon 15 in 49 tumors negative for BRAF(V600) mutations as well as driver mutations in KIT, NRAS, GNAQ, and GNA11, showed that two (4%) harbored L597 mutations and another two involved BRAF D594 and K601 mutations. In vitro signaling induced by L597R/S/Q mutants was suppressed by mitogen-activated protein (MAP)/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibition. A patient with BRAF(L597S) mutant metastatic melanoma responded significantly to treatment with the MEK inhibitor, TAK-733. Collectively, these data show clinical significance to BRAF(L597) mutations in melanoma.
This study shows that cells harboring BRAF(L597R) mutants are sensitive to MEK inhibitor treatment, providing a rationale for routine screening and therapy of BRAF(L597R)-mutant melanoma.
对于携带 BRAF 或 KIT 特定驱动突变的转移性黑色素瘤，激酶抑制剂已被接受为治疗方法，但只有 40% 到 50%的病例呈阳性。为了发现其他潜在的可靶向突变，我们对高度侵袭性的 BRAF(V600)和 KIT(W557、V559、L576、K642 和 D816)野生型黑色素瘤进行了全基因组测序。令人惊讶的是，我们在 BRAF 外显子 15 中发现了一个体细胞 BRAF(L597R)突变。对 49 个 BRAF(V600)突变阴性以及 KIT、NRAS、GNAQ 和 GNA11 驱动突变阴性的肿瘤进行 BRAF 外显子 15 分析显示，其中两个（4%）携带 L597 突变，另外两个涉及 BRAF D594 和 K601 突变。体外信号诱导 L597R/S/Q 突变体引起的信号被丝裂原激活蛋白（MAP）/细胞外信号调节激酶（ERK）激酶（MEK）抑制所抑制。一名携带 BRAF(L597S)突变转移性黑色素瘤的患者对 MEK 抑制剂 TAK-733 的治疗反应显著。总的来说，这些数据表明 BRAF(L597)突变在黑色素瘤中具有临床意义。
本研究表明，携带 BRAF(L597R)突变的细胞对 MEK 抑制剂治疗敏感，为常规筛查和 BRAF(L597R)突变黑色素瘤的治疗提供了依据。
