Dabrafenib; preclinical characterization, increased efficacy when combined with trametinib, while BRAF/MEK tool combination reduced skin lesions.
Dabrafenib; preclinical characterization, increased efficacy when combined with trametinib, while BRAF/MEK tool combination reduced skin lesions.
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DOI：
10.1371/journal.pone.0067583
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Laquerre SG
中科院分区：
文献类型：
--
作者：
King AJ;Arnone MR;Bleam MR;Moss KG;Yang J;Fedorowicz KE;Smitheman KN;Erhardt JA;Hughes-Earle A;Kane-Carson LS;Sinnamon RH;Qi H;Rheault TR;Uehling DE;Laquerre SG
丝裂原活化蛋白激酶(MAPK)途径的激活与多种类型的人类癌症有关。在黑色素瘤、结直肠癌、卵巢癌、乳头状甲状腺癌和胆管细胞癌中，BRAF基因突变可激活MAPK信号并绕过对上游刺激的需要。在这份报告中，我们描述了新型、有效和选择性的BRAF抑制剂达普拉非尼(GSK2118436)。达普拉非尼抑制BRAFV600E激酶活性导致MEK和ERK磷酸化减少，并通过最初的G1期细胞周期停滞抑制细胞增殖，随后细胞死亡。在含有BRAFV600E的人黑色素瘤异种移植模型中，口服达普拉非尼抑制ERK激活，下调Ki67，上调p27，导致肿瘤生长抑制。然而，与其他BRAF抑制剂一样，达普拉非尼也通过CRAF(RAF1)信号通路诱导野生型BRAF细胞中MAPK通路的激活，这可能解释了使用BRAF抑制剂治疗的患者发生鳞状细胞癌和角化棘皮瘤的原因。为了解决这个问题，我们发现同时使用BRAF和MEK抑制剂可以消除BRAF抑制剂诱导的细胞内矛盾的MAPK信号，减少大鼠皮肤损伤的发生，并在小鼠模型中加强对人类肿瘤异种生长的抑制。综上所述，我们的研究结果为达普拉非尼作为一种特异性和高效的BRAF抑制剂的临床前概念提供了证据，并为其与MEK抑制剂联合使用时的潜在临床益处提供了证据。
Mitogen-Activated Protein Kinase (MAPK) pathway activation has been implicated in many types of human cancer. BRAF mutations that constitutively activate MAPK signalling and bypass the need for upstream stimuli occur with high prevalence in melanoma, colorectal carcinoma, ovarian cancer, papillary thyroid carcinoma, and cholangiocarcinoma. In this report we characterize the novel, potent, and selective BRAF inhibitor, dabrafenib (GSK2118436). Cellular inhibition of BRAFV600E kinase activity by dabrafenib resulted in decreased MEK and ERK phosphorylation and inhibition of cell proliferation through an initial G1 cell cycle arrest, followed by cell death. In a BRAFV600E-containing xenograft model of human melanoma, orally administered dabrafenib inhibited ERK activation, downregulated Ki67, and upregulated p27, leading to tumor growth inhibition. However, as reported for other BRAF inhibitors, dabrafenib also induced MAPK pathway activation in wild-type BRAF cells through CRAF (RAF1) signalling, potentially explaining the squamous cell carcinomas and keratoacanthomas arising in patients treated with BRAF inhibitors. In addressing this issue, we showed that concomitant administration of BRAF and MEK inhibitors abrogated paradoxical BRAF inhibitor-induced MAPK signalling in cells, reduced the occurrence of skin lesions in rats, and enhanced the inhibition of human tumor xenograft growth in mouse models. Taken together, our findings offer preclinical proof of concept for dabrafenib as a specific and highly efficacious BRAF inhibitor and provide evidence for its potential clinical benefits when used in combination with a MEK inhibitor.
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影响因子：
64.5
作者：
Heidorn SJ;Milagre C;Whittaker S;Nourry A;Niculescu-Duvas I;Dhomen N;Hussain J;Reis-Filho JS;Springer CJ;Pritchard C;Marais R
通讯作者：
Marais R
影响因子：
5.7
作者：
Carnahan, Josette;Beltran, Pedro J.;Burgess, Teresa L.
通讯作者：
Burgess, Teresa L.
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
64.8
作者：
Johannessen, Cory M.;Boehm, Jesse S.;Kim, So Young;Thomas, Sapana R.;Wardwell, Leslie;Johnson, Laura A.;Emery, Caroline M.;Stransky, Nicolas;Cogdill, Alexandria P.;Barretina, Jordi;Caponigro, Giordano;Hieronymus, Haley;Murray, Ryan R.;Salehi-Ashtiani, Kourosh;Hill, David E.;Vidal, Marc;Zhao, Jean J.;Yang, Xiaoping;Alkan, Ozan;Kim, Sungjoon;Harris, Jennifer L.;Wilson, Christopher J.;Myer, Vic E.;Finan, Peter M.;Root, David E.;Roberts, Thomas M.;Golub, Todd;Flaherty, Keith T.;Dummer, Reinhard;Weber, Barbara L.;Sellers, William R.;Schlegel, Robert;Wargo, Jennifer A.;Hahn, William C.;Garraway, Levi A.
通讯作者：
Garraway, Levi A.
影响因子：
--
作者：
Hong, David S.;Reddy, Srini B.;Kurzrock, Razelle
通讯作者：
Kurzrock, Razelle