Wong Deborah J L, Robert Lidia, Atefi Mohammad S, Lassen Amanda, Avarappatt Geetha, Cerniglia Michael, Avramis Earl, Tsoi Jennifer, Foulad David, Graeber Thomas G, Comin-Anduix Begonya, Samatar Ahmed, Lo Roger S, Ribas Antoni
Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles (UCLA), 11-934 Factor Building, Los Angeles, CA, USA.
Mol Cancer. 2014 Aug 20;13:194. doi: 10.1186/1476-4598-13-194.
In melanoma, dysregulation of the MAPK pathway, usually via BRAF(V600) or NRAS(Q61) somatic mutations, leads to constitutive ERK signaling. While BRAF inhibitors are initially effective for BRAF-mutant melanoma, no FDA-approved targeted therapies exist for BRAF-inhibitor-resistant BRAF(V600), NRAS mutant, or wild-type melanoma.
The 50% inhibitory concentration (IC50) of SCH772984, a novel inhibitor of ERK1/2, was determined in a panel of 50 melanoma cell lines. Effects on MAPK and AKT signaling by western blotting and cell cycle by flow cytometry were determined.
Sensitivity fell into three groups: sensitive, 50% inhibitory concentration (IC50) < 1 μM; intermediately sensitive, IC50 1-2 μM; and resistant, >2 μM. Fifteen of 21 (71%) BRAF mutants, including 4 with innate vemurafenib resistance, were sensitive to SCH772984. All three (100%) BRAF/NRAS double mutants, 11 of 14 (78%) NRAS mutants and 5 of 7 (71%) wild-type melanomas were sensitive. Among BRAF(V600) mutants with in vitro acquired resistance to vemurafenib, those with MAPK pathway reactivation as the mechanism of resistance were sensitive to SCH772984. SCH772984 caused G1 arrest and induced apoptosis.
Combining vemurafenib and SCH722984 in BRAF mutant melanoma was synergistic in a majority of cell lines and significantly delayed the onset of acquired resistance in long term in vitro assays. Therefore, SCH772984 may be clinically applicable as a treatment for non-BRAF mutant melanoma or in BRAF-mutant melanoma with innate or acquired resistance, alone or in combination with BRAF inhibitors.
在黑色素瘤中，丝裂原活化蛋白激酶（MAPK）通路的失调通常是通过BRAF（V600）或NRAS（Q61）体细胞突变，导致组成性ERK信号传导。虽然BRAF抑制剂最初对BRAF突变型黑色素瘤有效，但对于BRAF抑制剂耐药的BRAF（V600）、NRAS突变型或野生型黑色素瘤，尚无美国食品药品监督管理局（FDA）批准的靶向治疗方法。
在一组50个黑色素瘤细胞系中测定新型ERK1/2抑制剂SCH772984的50%抑制浓度（IC50）。通过蛋白质印迹法测定对MAPK和AKT信号传导的影响，通过流式细胞术测定对细胞周期的影响。
敏感性分为三组：敏感，50%抑制浓度（IC50）<1μM；中度敏感，IC50为1 - 2μM；耐药，>2μM。21个BRAF突变体中的15个（71%），包括4个对维莫非尼具有天然耐药性的突变体，对SCH772984敏感。所有3个（100%）BRAF/NRAS双突变体、14个NRAS突变体中的11个（78%）以及7个野生型黑色素瘤中的5个（71%）均敏感。在对维莫非尼具有体外获得性耐药的BRAF（V600）突变体中，那些以MAPK通路重新激活作为耐药机制的突变体对SCH772984敏感。SCH772984导致G1期阻滞并诱导凋亡。
在BRAF突变型黑色素瘤中，将维莫非尼和SCH722984联合使用在大多数细胞系中具有协同作用，并且在长期体外试验中显著延迟了获得性耐药的发生。因此，SCH772984可能在临床上适用于治疗非BRAF突变型黑色素瘤或具有天然或获得性耐药的BRAF突变型黑色素瘤，单独使用或与BRAF抑制剂联合使用。
