Combination therapy with vemurafenib (PLX4032/RG7204) and metformin in melanoma cell lines with distinct driver mutations.
Combination therapy with vemurafenib (PLX4032/RG7204) and metformin in melanoma cell lines with distinct driver mutations.
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DOI：
10.1186/1479-5876-9-76
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发表时间：
2011-05-24
影响因子：
7.4
通讯作者：
Ribas A
中科院分区：
文献类型：
--
作者：
Niehr F;von Euw E;Attar N;Guo D;Matsunaga D;Sazegar H;Ng C;Glaspy JA;Recio JA;Lo RS;Mischel PS;Comin-Anduix B;Ribas A
MAPK和LKB1-AMPK能量传感器通路之间的分子联系表明，在黑色素瘤细胞系中，MAPK致癌基因抑制和AMPK代谢调节的联合作用比单独操作更有效。BRAF抑制剂vemurafenib（原PLX4032）和二甲双胍联合应用于一组具有明确BRAF和NRAS突变的人类黑色素瘤细胞系，测试其对细胞活力、细胞周期和凋亡的影响。Western blot检测MAPK、PI3K-AKT和LKB1-AMPK通路中的信号分子。单剂二甲双胍抑制了19个细胞系中的12个细胞系的增殖，与BRAF突变状态无关，但在一个NRASQ61K突变细胞系中，二甲双胍强烈刺激了细胞生长。二甲双胍联合vemurafenib在11个BRAFV600E突变体中的6个中观察到协同抗增殖作用，包括在2个BRAFV600E突变体黑色素瘤细胞系中的高度协同作用。在一些细胞系中发现了拮抗作用，特别是在BRAFV600E突变细胞系中，对单药vemurafenib具有抗性。8个BRAF野生型细胞系中有7个对该组合具有微弱的协同抗增殖作用，1个细胞系对该组合具有高度拮抗作用。不同的效果不依赖于对每种药物的敏感性，对细胞周期或信号通路的影响。vemurafenib与二甲双胍联用对BRAFV600E突变细胞系具有更强的抗增殖作用。然而，vemurafenib和二甲双胍协同作用或拮抗作用的决定因素需要更详细地了解，然后再进行任何潜在的临床应用。
A molecular linkage between the MAPK and the LKB1-AMPK energy sensor pathways suggests that combined MAPK oncogene inhibition and metabolic modulation of AMPK would be more effective than either manipulation alone in melanoma cell lines. The combination of the BRAF inhibitor vemurafenib (formerly PLX4032) and metformin were tested against a panel of human melanoma cell lines with defined BRAF and NRAS mutations for effects on viability, cell cycle and apoptosis. Signaling molecules in the MAPK, PI3K-AKT and LKB1-AMPK pathways were studied by Western blot. Single agent metformin inhibited proliferation in 12 out of 19 cell lines irrespective of the BRAF mutation status, but in one NRASQ61K mutant cell line it powerfully stimulated cell growth. Synergistic anti-proliferative effects of the combination of metformin with vemurafenib were observed in 6 out of 11 BRAFV600E mutants, including highly synergistic effects in two BRAFV600E mutant melanoma cell lines. Antagonistic effects were noted in some cell lines, in particular in BRAFV600E mutant cell lines resistant to single agent vemurafenib. Seven out of 8 BRAF wild type cell lines showed marginally synergistic anti-proliferative effects with the combination, and one cell line had highly antagonistic effects with the combination. The differential effects were not dependent on the sensitivity to each drug alone, effects on cell cycle or signaling pathways. The combination of vemurafenib and metformin tended to have stronger anti-proliferative effects on BRAFV600E mutant cell lines. However, determinants of vemurafenib and metformin synergism or antagonism need to be understood with greater detail before any potential clinical utility of this combination.
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DOI：
10.1016/j.bbrc.2010.06.052
发表时间：
2010-07-16
影响因子：
3.1
作者：
Woodard, Jennifer;Platanias, Leonidas C.
通讯作者：
Platanias, Leonidas C.
影响因子：
56.9
作者：
Shaw, RJ;Lamia, KA;Cantley, LC
通讯作者：
Cantley, LC
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：
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：
3.7
作者：
Esteve-Puig R;Canals F;Colomé N;Merlino G;Recio JA
通讯作者：
Recio JA