Vemurafenib resistance reprograms melanoma cells towards glutamine dependence.
Vemurafenib resistance reprograms melanoma cells towards glutamine dependence.
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DOI：
10.1186/s12967-015-0581-2
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发表时间：
2015-07-03
影响因子：
7.4
通讯作者：
Kong M
中科院分区：
文献类型：
--
作者：
Hernandez-Davies JE;Tran TQ;Reid MA;Rosales KR;Lowman XH;Pan M;Moriceau G;Yang Y;Wu J;Lo RS;Kong M
V600 BRAF突变驱动大约50%的转移性黑素瘤，其可以通过BRAF抑制剂（BRAFi）以及基于耐药机制的BRAF和MEK抑制剂的组合（BRAFi + MEKi）进行治疗靶向。尽管联合治疗已显示出提供上级临床获益，但获得性耐药仍然普遍存在，并限制了总体生存获益。最近的研究表明，致癌的变化可以导致肿瘤细胞代谢的改变，使细胞对营养物质上瘾，如氨基酸谷氨酰胺。在这里，我们评估了获得性耐药的黑色素瘤细胞是否表现出谷氨酰胺依赖性，以及谷氨酰胺代谢是否可以成为治疗耐药细胞的潜在分子靶点。使用同基因BRAFi敏感性亲本V600 BRAF突变黑素瘤细胞系和抗性（通过用维罗非尼长期处理衍生）亚系来评估谷氨酰胺摄取和对谷氨酰胺剥夺的敏感性的差异。为了评估更广泛的抗性机制，还研究了其中亚系对BRAFi + MEKi具有抗性的等基因对。由于抗性细胞表现出对谷氨酰胺缺乏的敏感性增加，我们使用谷氨酰胺酶抑制剂BPTES [双-2-（5苯乙酰氨基-1，2，4-噻二唑-2-基）乙基硫醚]和L-L-DON（6-重氮-5-氧代-1-正亮氨酸）在体外和体内处理MAPK途径抑制剂（MAPKi）抗性细胞群体。我们证明了MAPKi获得性抗性细胞摄取了更大量的谷氨酰胺，并且对谷氨酰胺剥夺的敏感性比其MAPKi敏感的对应物增加。此外，发现BPTES和L-DON在体外比亲本细胞群更有效地降低MAPKi抗性亚系的细胞存活。我们还表明，在突变型NRAS驱动的耐药性中，突变型NRAS对谷氨酰胺成瘾至关重要。当在体内测试时，我们发现来自抗性细胞的异种移植物比来自亲本细胞的异种移植物对BPTES或L-DON治疗更敏感。我们的研究是针对谷氨酰胺代谢作为抑制黑色素瘤中获得性MAPKi抗性的替代策略的潜力的概念验证。
V600BRAF mutations drive approximately 50% of metastatic melanoma which can be therapeutically targeted by BRAF inhibitors (BRAFi) and, based on resistance mechanisms, the combination of BRAF and MEK inhibitors (BRAFi + MEKi). Although the combination therapy has been shown to provide superior clinical benefits, acquired resistance is still prevalent and limits the overall survival benefits. Recent work has shown that oncogenic changes can lead to alterations in tumor cell metabolism rendering cells addicted to nutrients, such as the amino acid glutamine. Here, we evaluated whether melanoma cells with acquired resistance display glutamine dependence and whether glutamine metabolism can be a potential molecular target to treat resistant cells. Isogenic BRAFi sensitive parental V600BRAF mutant melanoma cell lines and resistant (derived by chronic treatment with vemurafenib) sub-lines were used to assess differences in the glutamine uptake and sensitivity to glutamine deprivation. To evaluate a broader range of resistance mechanisms, isogenic pairs where the sub-lines were resistant to BRAFi + MEKi were also studied. Since resistant cells demonstrated increased sensitivity to glutamine deficiency, we used glutaminase inhibitors BPTES [bis-2-(5 phenylacetamido-1, 2, 4-thiadiazol-2-yl) ethyl sulfide] and L–L-DON (6-Diazo-5-oxo-l-norleucine) to treat MAPK pathway inhibitor (MAPKi) resistant cell populations both in vitro and in vivo. We demonstrated that MAPKi-acquired resistant cells uptook greater amounts of glutamine and have increased sensitivity to glutamine deprivation than their MAPKi-sensitive counterparts. In addition, it was found that both BPTES and L-DON were more effective at decreasing cell survival of MAPKi-resistant sub-lines than parental cell populations in vitro. We also showed that mutant NRAS was critical for glutamine addiction in mutant NRAS driven resistance. When tested in vivo, we found that xenografts derived from resistant cells were more sensitive to BPTES or L-DON treatment than those derived from parental cells. Our study is a proof-of-concept for the potential of targeting glutamine metabolism as an alternative strategy to suppress acquired MAPKi-resistance in melanoma.
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影响因子：
28.2
作者：
Parmenter TJ;Kleinschmidt M;Kinross KM;Bond ST;Li J;Kaadige MR;Rao A;Sheppard KE;Hugo W;Pupo GM;Pearson RB;McGee SL;Long GV;Scolyer RA;Rizos H;Lo RS;Cullinane C;Ayer DE;Ribas A;Johnstone RW;Hicks RJ;McArthur GA
通讯作者：
McArthur GA
影响因子：
28.2
作者：
Shi H;Hugo W;Kong X;Hong A;Koya RC;Moriceau G;Chodon T;Guo R;Johnson DB;Dahlman KB;Kelley MC;Kefford RF;Chmielowski B;Glaspy JA;Sosman JA;van Baren N;Long GV;Ribas A;Lo RS
通讯作者：
Lo RS
影响因子：
4
作者：
Spagnolo F;Ghiorzo P;Orgiano L;Pastorino L;Picasso V;Tornari E;Ottaviano V;Queirolo P
通讯作者：
Queirolo P
影响因子：
7.4
作者：
Søndergaard JN;Nazarian R;Wang Q;Guo D;Hsueh T;Mok S;Sazegar H;MacConaill LE;Barretina JG;Kehoe SM;Attar N;von Euw E;Zuckerman JE;Chmielowski B;Comin-Anduix B;Koya RC;Mischel PS;Lo RS;Ribas A
通讯作者：
Ribas A
影响因子：
11.2
作者：
Seltzer MJ;Bennett BD;Joshi AD;Gao P;Thomas AG;Ferraris DV;Tsukamoto T;Rojas CJ;Slusher BS;Rabinowitz JD;Dang CV;Riggins GJ
通讯作者：
Riggins GJ