Patient-derived models of acquired resistance can identify effective drug combinations for cancer.
Patient-derived models of acquired resistance can identify effective drug combinations for cancer.
复制标题
DOI：
10.1126/science.1254721
复制
发表时间：
2014-12-19
期刊：
影响因子：
--
通讯作者：
Engelman JA
中科院分区：
文献类型：
--
作者：
Crystal AS;Shaw AT;Sequist LV;Friboulet L;Niederst MJ;Lockerman EL;Frias RL;Gainor JF;Amzallag A;Greninger P;Lee D;Kalsy A;Gomez-Caraballo M;Elamine L;Howe E;Hur W;Lifshits E;Robinson HE;Katayama R;Faber AC;Awad MM;Ramaswamy S;Mino-Kenudson M;Iafrate AJ;Benes CH;Engelman JA
靶向癌症治疗已经产生了实质性的临床反应，但大多数肿瘤对这些药物产生了耐药性。在这里，我们描述了一个药物基因组学平台，有助于快速发现可以克服耐药性的药物组合。我们建立了来自肺癌患者活检样本的细胞培养模型，这些患者在接受EGFR或ALK酪氨酸激酶抑制剂治疗时疾病进展，然后对这些细胞进行遗传分析和药理学筛选。确定了多种有效的药物组合。例如，ALK和MEK抑制剂的组合在已经发生MAP2K1激活突变的ALK阳性耐药肿瘤中具有活性，并且EGFR和FGFR抑制剂的组合在具有FGFR 3中的新突变的EGFR突变体耐药癌症中具有活性。ALK和SRC联合抑制在几种ALK驱动的患者衍生模型中有效，这一结果无法单独通过遗传分析预测。随着进一步的改进，这种策略可以帮助指导个体患者的治疗选择。
Targeted cancer therapies have produced substantial clinical responses but most tumors develop resistance to these drugs. Here we describe a pharmacogenomic platform that facilitates rapid discovery of drug combinations that can overcome resistance. We established cell culture models derived from biopsy samples of lung cancer patients whose disease had progressed while on treatment with EGFR or ALK tyrosine kinase inhibitors and then subjected these cells to genetic analyses and a pharmacological screen. Multiple effective drug combinations were identified. For example, the combination of ALK and MEK inhibitors was active in an ALK-positive resistant tumor that had developed a MAP2K1 activating mutation, and the combination of EGFR and FGFR inhibitors was active in an EGFR mutant resistant cancer with a novel mutation in FGFR3. Combined ALK and SRC inhibition was effective in several ALK-driven patient-derived models, a result not predicted by genetic analysis alone. With further refinements, this strategy could help direct therapeutic choices for individual patients.
登录
查看更多内容
影响因子：
28.2
作者：
Friboulet L;Li N;Katayama R;Lee CC;Gainor JF;Crystal AS;Michellys PY;Awad MM;Yanagitani N;Kim S;Pferdekamper AC;Li J;Kasibhatla S;Sun F;Sun X;Hua S;McNamara P;Mahmood S;Lockerman EL;Fujita N;Nishio M;Harris JL;Shaw AT;Engelman JA
通讯作者：
Engelman JA
双ALK和EGFR抑制靶向ALK重排的肺癌中获得对酪氨酸激酶抑制剂Crizotinib的获得性机制。
DOI：
10.1016/j.lungcan.2013.09.019
发表时间：
2014-01
期刊：
Lung cancer (Amsterdam, Netherlands)
影响因子：
--
作者：
Yamaguchi N;Lucena-Araujo AR;Nakayama S;de Figueiredo-Pontes LL;Gonzalez DA;Yasuda H;Kobayashi S;Costa DB
通讯作者：
Costa DB
有效使用 PI3K 和 MEK 抑制剂治疗突变型 Kras G12D 和 PIK3CA H1047R 小鼠肺癌。
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
64.8
作者：
BAGRODIA, S;CHACKALAPARAMPIL, I;SHALLOWAY, D
通讯作者：
SHALLOWAY, D
影响因子：
50.3
作者：
Walters, Denise K.;Mercher, Thomas;Druker, Brian J.
通讯作者：
Druker, Brian J.