Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion.
Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion.
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DOI：
10.1038/nature11183
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发表时间：
2012-07-26
期刊：
影响因子：
64.8
通讯作者：
Golub, Todd R.
中科院分区：
文献类型：
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作者：
Straussman, Ravid;Morikawa, Teppei;Shee, Kevin;Barzily-Rokni, Michal;Qian, Zhi Rong;Du, Jinyan;Davis, Ashli;Mongare, Margaret M.;Gould, Joshua;Frederick, Dennie T.;Cooper, Zachary A.;Chapman, Paul B.;Solit, David B.;Ribas, Antoni;Lo, Roger S.;Flaherty, Keith T.;Ogino, Shuji;Wargo, Jennifer A.;Golub, Todd R.
耐药性仍然是癌症患者治疗中令人烦恼的问题。虽然许多研究都集中在耐药的细胞自主机制上，但我们假设肿瘤微环境可能赋予对治疗的先天抗性。在这里，我们开发了一个共培养系统，系统地分析了23种基质细胞类型影响45种癌细胞系对35种抗癌药物的先天耐药性的能力。我们发现，基质介导的耐药性是令人惊讶的普遍-特别是靶向药物。我们进一步描述了基质介导的BRAF突变型黑色素瘤对RAF抑制的抗性，因为这些患者中的大多数表现出一定程度的先天抗性。蛋白质组学分析表明，生长因子肝细胞生长因子（HGF）的基质分泌导致HGF受体MET的激活，MAPK和PI 3 K/AKT通路的再激活，以及对RAF抑制的立即抗性。免疫组化证实了BRAF突变型黑色素瘤患者的基质HGF表达，以及基质HGF表达与先天性治疗抵抗之间的统计学显著相关性。RAF和MET的双重抑制导致耐药性逆转，表明RAF/MET联合治疗是BRAF突变型黑色素瘤的潜在治疗策略。在BRAF突变的结肠直肠和胶质母细胞瘤细胞系的一个子集中发现了类似的耐药机制。更一般地说，这些研究表明，肿瘤微环境相互作用的系统解剖可能揭示耐药的重要机制。
Drug resistance remains a vexing problem in the treatment of cancer patients. While many studies have focused on cell autonomous mechanisms of drug resistance, we hypothesized that the tumor microenvironment may confer innate resistance to therapy. Here we developed a co-culture system to systematically assay the ability of 23 stromal cell types to influence the innate resistance of 45 cancer cell lines to 35 anti-cancer drugs. We found that stroma-mediated resistance is surprisingly common – particularly to targeted agents. We further characterized the stroma-mediated resistance of BRAF-mutant melanoma to RAF inhibition because most of these patients exhibit some degree of innate resistance. Proteomic analysis showed that stromal secretion of the growth factor hepatocyte growth factor (HGF) resulted in activation of the HGF receptor MET, reactivation of the MAPK and PI3K/AKT pathways, and immediate resistance to RAF inhibition. Immunohistochemistry confirmed stromal HGF expression in patients with BRAF-mutant melanoma and a statistically significant correlation between stromal HGF expression and innate resistance to treatment. Dual inhibition of RAF and MET resulted in reversal of drug resistance, suggesting RAF/MET combination therapy as a potential therapeutic strategy for BRAF-mutant melanoma. A similar resistance mechanism was uncovered in a subset of BRAF-mutant colorectal and glioblastoma cell lines. More generally, these studies indicate that the systematic dissection of tumor-microenvironment interactions may reveal important mechanisms underlying drug resistance.
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影响因子：
9.7
作者：
Kammula, Udal S.;Kuntz, Eleanor J.;Weiser, Martin R.
通讯作者：
Weiser, Martin R.
影响因子：
46.9
作者：
Du, Jinyan;Bernasconi, Paula;Clauser, Karl R.;Mani, D. R.;Finn, Stephen P.;Beroukhim, Rameen;Burns, Melissa;Julian, Bina;Peng, Xiao P.;Hieronymus, Haley;Maglathlin, Rebecca L.;Lewis, Timothy A.;Liau, Linda M.;Nghiemphu, Phioanh;Mellinghoff, Ingo K.;Louis, David N.;Loda, Massimo;Carr, Steven A.;Kung, Andrew L.;Golub, Todd R.
通讯作者：
Golub, Todd R.
影响因子：
64.8
作者：
通讯作者：
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影响因子：
28.2
作者：
Corcoran RB;Ebi H;Turke AB;Coffee EM;Nishino M;Cogdill AP;Brown RD;Della Pelle P;Dias-Santagata D;Hung KE;Flaherty KT;Piris A;Wargo JA;Settleman J;Mino-Kenudson M;Engelman JA
通讯作者：
Engelman JA
影响因子：
82.9
作者：
通讯作者：
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