Tumor cell-intrinsic phenotypic plasticity facilitates adaptive cellular reprogramming driving acquired drug resistance.
Tumor cell-intrinsic phenotypic plasticity facilitates adaptive cellular reprogramming driving acquired drug resistance.
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DOI：
10.1007/s12079-017-0435-1
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发表时间：
2018-03
影响因子：
4.1
通讯作者：
Schaider H
中科院分区：
文献类型：
--
作者：
Hammerlindl H;Schaider H
对成功的癌症新治疗策略的热情往往很快被耐药性的发展所抑制。对于使用酪氨酸激酶抑制剂治疗EGFR或BRAF突变型癌症的靶向治疗来说，这是正确的，但对于免疫治疗来说，这也是一个日益被认识到的问题。肿瘤基因型和表型特征的异质性是肿瘤成功治疗的主要障碍之一。从历史上看，耐药性的驱动因素已经在遗传水平上被怀疑和发现，突变要么存在于癌细胞亚群中，要么重新出现以介导耐药性。与此相反，我们的研究小组和其他研究人员发现了一种非突变的适应性反应，导致可逆的、耐药的、缓慢循环的表型，这种表型在永久性耐药性出现之前，由长期的药物暴露引发。最近，研究描述了最初可逆的转录重编程对获得性耐药发展的重要性，确定了慢循环表型存活的重要因素，并研究了突变和非突变耐药机制的关系。然而，突变和适应性耐药与现有体外模型和临床观察到的反应模式之间的联系和相对重要性仍然不明确。在这篇综述中，我们关注癌细胞的适应性内在表型可塑性，它导致耐药缓慢循环状态，最终过渡到永久耐药，并基于现有文献提出了一个通用模型，来描述获得性耐药的发展。
The enthusiasm about successful novel therapeutic strategies in cancer is often quickly dampened by the development of drug resistance. This is true for targeted therapies using tyrosine kinase inhibitors for EGFR or BRAF mutant cancers, but is also an increasingly recognized problem for immunotherapies. One of the major obstacles of successful cancer therapy is tumor heterogeneity of genotypic and phenotypic features. Historically, drivers for drug resistance have been suspected and found on the genetic level, with mutations either being pre-existing in a subset of cancer cells or emerging de novo to mediate drug resistance. In contrast to that, our group and others identified a non-mutational adaptive response, resulting in a reversible, drug tolerant, slow cycling phenotype that precedes the emergence of permanent drug resistance and is triggered by prolonged drug exposure. More recently, studies described the importance of initially reversible transcriptional reprogramming for the development of acquired drug resistance, identified factors important for the survival of the slow cycling phenotype and investigated the relationship of mutational and non-mutational resistance mechanisms. However, the connection and relative importance of mutational and adaptive drug resistance in relation to the in vitro models at hand and the clinically observed response patterns remains poorly defined. In this review we focus on adaptive intrinsic phenotypic plasticity in cancer cells that leads to the drug tolerant slow cycling state, which eventually transitions to permanent resistance, and propose a general model based on current literature, to describe the development of acquired drug resistance.
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DOI：
10.1056/nejmoa1502309
发表时间：
2015-08-20
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hyman DM;Puzanov I;Subbiah V;Faris JE;Chau I;Blay JY;Wolf J;Raje NS;Diamond EL;Hollebecque A;Gervais R;Elez-Fernandez ME;Italiano A;Hofheinz RD;Hidalgo M;Chan E;Schuler M;Lasserre SF;Makrutzki M;Sirzen F;Veronese ML;Tabernero J;Baselga J
通讯作者：
Baselga J
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
8
作者：
通讯作者：
--
影响因子：
15.8
作者：
Greulich H;Chen TH;Feng W;Jänne PA;Alvarez JV;Zappaterra M;Bulmer SE;Frank DA;Hahn WC;Sellers WR;Meyerson M
通讯作者：
Meyerson M
影响因子：
82.9
作者：
Hata AN;Niederst MJ;Archibald HL;Gomez-Caraballo M;Siddiqui FM;Mulvey HE;Maruvka YE;Ji F;Bhang HE;Krishnamurthy Radhakrishna V;Siravegna G;Hu H;Raoof S;Lockerman E;Kalsy A;Lee D;Keating CL;Ruddy DA;Damon LJ;Crystal AS;Costa C;Piotrowska Z;Bardelli A;Iafrate AJ;Sadreyev RI;Stegmeier F;Getz G;Sequist LV;Faber AC;Engelman JA
通讯作者：
Engelman JA