在一項(xiàng)新研究中，研究人員發(fā)現(xiàn)發(fā)生罕見(jiàn)BRAF基因突變的黑色素瘤患者對(duì)MEK抑制劑藥物作出反應(yīng),，這就為開(kāi)展日常篩選和治療攜帶BRAF L597突變的黑色素瘤患者提供理論基礎(chǔ),。
在大約40%到50%的黑色素瘤中，經(jīng)常發(fā)生BRAF V600E或KIT突變,。阻斷或抑制BRAF V600E的藥物最近被批準(zhǔn)用來(lái)治療攜帶這些突變的黑色素瘤患者,。然而，目前還沒(méi)有有效的方法來(lái)治療野生型黑色素瘤,，因?yàn)樗鼈儾淮嬖谶@些驅(qū)動(dòng)突變(driver mutation),。
為了揭示其他潛在的靶向突變,，研究人員研究一名75歲的患有侵襲性黑色素瘤并且沒(méi)有發(fā)生BRAF V600E突變的病人。他們進(jìn)行腫瘤全基因組測(cè)序,，同時(shí)也對(duì)來(lái)自匹配血液中的DNA進(jìn)行測(cè)序,，從而證實(shí)存在BRAF L597突變。
為了確定當(dāng)只測(cè)定BRAF V600位點(diǎn)的突變有多少類(lèi)似的突變可能被忽略時(shí),，他們又分析了49個(gè)BRAF V600未發(fā)生突變的腫瘤樣品的突變情況和NRAS和KIT上的頻發(fā)突變(recurrent mutation)情形,。他們發(fā)現(xiàn)兩個(gè)腫瘤樣品(占4%)中存在BRAF L597突變，還有一個(gè)腫瘤樣品發(fā)生BRAF K601E突變,。
BRAF L597和K601 位點(diǎn)與V600位點(diǎn)相鄰,。因?yàn)閂600突變體對(duì)BRAF抑制劑和MEK抑制劑藥物都敏感，所以研究人員測(cè)試了BRAF抑制劑藥物維羅非尼(vemurafenib)和一種MEK抑制劑藥物是否能夠抑制在細(xì)胞系中這些突變誘導(dǎo)的細(xì)胞增殖信號(hào),。MEK抑制劑導(dǎo)致這種信號(hào)的顯著性關(guān)閉,，提示著攜帶BRAF L597和K601突變的腫瘤可能受益于MEK抑制劑的治療。
為了證實(shí)這種猜測(cè),，一名69歲的患有轉(zhuǎn)移性黑色素瘤而且攜帶BRAF L597S突變的病人在利用一種被稱作TAK-733的MEK抑制劑進(jìn)行兩輪治療之后,，體內(nèi)腫瘤發(fā)生顯著性萎縮。
研究人員相信這些數(shù)據(jù)證實(shí)BRAF L597突變?cè)诤谏亓鲋写嬖诜浅Ｖ匾呐R床意義,，不過(guò)還需進(jìn)一步開(kāi)展研究來(lái)證實(shí)這些發(fā)現(xiàn),。(生物谷：Bioon.com)
本文編譯自Uncommon BRAF mutation in melanoma sensitive to MEK inhibitor drug therapy
doi: 10.1038/ni.2365
PMC:
PMID:
BRAF L597 mutations in melanoma are associated with sensitivity to MEK inhibitors
Kimberly B Dahlman1, Junfeng Xia2, Katie Hutchinson1, Charles Ng3, Donald Hucks4, Peilin Jia2, Mohammad Atefi3, Zengliu Su4, Suzanne Branch3, Pamela Lyle5, Donna J Hicks1, Viviana Bozon6, John A. Glaspy3, Neal Rosen7, David B Solit7, James L. Netterville8, Cindy L. Vnencak-Jones5, Jeffrey A. Sosman9, Antoni Ribas3, Zhongming Zhao2 and William Pao
Kinase inhibitors are accepted treatment for metastatic melanomas that harbor specific driver mutations in BRAF or KIT, but only 40-50% of cases are positive. To uncover other potential targetable mutations, we performed whole-genome sequencing of a highly aggressive BRAF (V600) and KIT (W557, V559, L576, K642, D816) wildtype 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 2 (4%) harbored L597 mutations and another 2 involved BRAF D594 and K601 mutations. In vitro signaling induced by L597R/S/Q mutants was suppressed by MEK inhibition. A patient with BRAF L597S mutant metastatic melanoma responded significantly to treatment with the MEK inhibitor, TAK-733. Collectively, these data demonstrate clinical significance to BRAF L597 mutations in melanoma.
