KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer.
KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer.
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DOI：
10.1016/j.cell.2017.01.020
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发表时间：
2017-02-23
期刊：
影响因子：
64.5
通讯作者：
Shannon K
中科院分区：
文献类型：
--
作者：
Burgess MR;Hwang E;Mroue R;Bielski CM;Wandler AM;Huang BJ;Firestone AJ;Young A;Lacap JA;Crocker L;Asthana S;Davis EM;Xu J;Akagi K;Le Beau MM;Li Q;Haley B;Stokoe D;Sampath D;Taylor BS;Evangelista M;Shannon K
研究对癌症治疗表现出异常反应的治疗“异常值”可以揭示药物敏感性的生物标志物。我们进行了临床前试验，研究在KrasG12D“敲入”小鼠中由逆转录病毒插入诱变产生的原发性鼠急性髓系白血病（AML），使用MEK抑制剂PD0325901（PD901）。一种异常的AML有反应，并在复发时表现出内在的耐药性。野生型（WT）Kras的缺失增强了优势克隆的适应性，并使其对MEK抑制敏感。同样，KRAS突变等位基因频率增加的人类结直肠癌细胞系对MAP激酶抑制更敏感，并且CRISPR - Cas9介导的用突变等位基因替换WT KRAS使杂合突变HCT116细胞对治疗敏感。在一个预先特征明确的晚期癌症患者队列中，1168名患者中有642名（55%）携带KRAS突变，表现出等位基因失衡。这些研究表明，Kras/KRAS基因座的系列遗传变化在癌症中很常见，并调节竞争适应性和MEK依赖性。
突变型和野生型KRAS等位基因剂量的失衡塑造了癌细胞快速生长和对MEK抑制剂治疗耐药之间的权衡，解释了抑制剂试验中遇到的挑战。
Investigating therapeutic “outliers” that show exceptional responses to anti-cancer treatment can uncover biomarkers of drug sensitivity. We performed preclinical trials investigating primary murine acute myeloid leukemias (AMLs) generated by retroviral insertional mutagenesis in KrasG12D “knock-in” mice with the MEK inhibitor PD0325901 (PD901). One outlier AML responded and exhibited intrinsic drug resistance at relapse. Loss of wild-type (WT) Kras enhanced the fitness of the dominant clone and rendered it sensitive to MEK inhibition. Similarly, human colorectal cancer cell lines with increased KRAS mutant allele frequency are more sensitive to MAP kinase inhibition, and CRISPR-Cas9-mediated replacement of WT KRAS with a mutant allele sensitized heterozygous mutant HCT116 cells to treatment. In a prospectively characterized cohort of patients with advanced cancer, 642 of 1168 (55%) with KRAS mutations exhibited allelic imbalance. These studies demonstrate that serial genetic changes at the Kras/KRAS locus are frequent in cancer, and modulate competitive fitness and MEK dependency. Imbalance in the dosage of mutant and wild-type KRAS allele shapes the tradeoff between rapid cancer cell growth and resistance to MEK inhibitor therapy, explaining challenges encountered during inhibitor trials.
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DOI：
10.1126/science.1226344
发表时间：
2012-10-12
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Iyer G;Hanrahan AJ;Milowsky MI;Al-Ahmadie H;Scott SN;Janakiraman M;Pirun M;Sander C;Socci ND;Ostrovnaya I;Viale A;Heguy A;Peng L;Chan TA;Bochner B;Bajorin DF;Berger MF;Taylor BS;Solit DB
通讯作者：
Solit DB
影响因子：
64.5
作者：
BREMNER, R;BALMAIN, A
通讯作者：
BALMAIN, A
使用下一代 DNA 测序数据进行变异发现和基因分型的框架。
影响因子：
30.8
作者：
通讯作者：
--
DOI：
10.1073/pnas.0905833106
发表时间：
2009-12-01
影响因子：
11.1
作者：
Emery, Caroline M.;Vijayendran, Krishna G.;Garraway, Levi A.
通讯作者：
Garraway, Levi A.
影响因子：
30.8
作者：
Haigis, Kevin M.;Kendall, Krystle R.;Jacks, Tyler
通讯作者：
Jacks, Tyler