KRAS Allelic Imbalance Enhances Fitness and Modulates MAP Kinase Dependence in Cancer

被引：152

作者：

Burgess, Michael R. ^{[1
]}

Hwang, Eugene ^{[2
]}

Mroue, Rana ^{[3
]}

Bielski, Craig M. ^{[4
]}

Wandler, Anica M. ^{[2
]}

Huang, Benjamin J. ^{[2
]}

Firestone, Ari J. ^{[2
]}

Young, Amy ^{[5
]}

Lacap, Jennifer A. ^{[5
]}

Crocker, Lisa ^{[5
]}

Asthana, Saurabh ^{[1
]}

Davis, Elizabeth M. ^{[6
]}

Xu, Jin ^{[2
]}

Akagi, Keiko ^{[7
]}

Le Beau, Michelle M. ^{[6
]}

Li, Qing ^{[8
]}

Haley, Benjamin ^{[9
]}

Stokoe, David ^{[3
]}

Sampath, Deepak ^{[5
]}

Taylor, Barry S. ^{[4
,10
,11
]}

Evangelista, Marie ^{[3
]}

Shannon, Kevin ^{[2
,12
]}

机构：

[1] Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA

[2] Univ Calif San Francisco, Dept Pediat, San Francisco, CA 94143 USA

[3] Genentech Inc, Dept Discovery Oncol, San Francisco, CA 94080 USA

[4] Mem Sloan Kettering Canc Ctr, Marie Josee & Henry R Kravis Ctr Mol Oncol, New York, NY 10065 USA

[5] Genentech Inc, Dept Translat Oncol, San Francisco, CA 94080 USA

[6] Univ Chicago, Dept Med, Hematol Oncol Sect, Chicago, IL 60637 USA

[7] Ohio State Univ, Dept Canc Biol & Genet, Columbus, OH 43210 USA

[8] Univ Michigan, Dept Med, Div Hematol Oncol, Ann Arbor, MI 48109 USA

[9] Genentech Inc, Dept Mol Biol, San Francisco, CA 94080 USA

[10] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[11] Mem Sloan Kettering Canc Ctr, Dept Epidemiol & Biostat, New York, NY 10065 USA

[12] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA

来源：

CELL | 2017年 / 168卷 / 05期

关键词：

ACUTE MYELOID-LEUKEMIA; ORAL MEK INHIBITOR; COPY NUMBER; K-RAS; LUNG-CANCER; DEVELOPMENTAL DEFECTS; TUMOR PROGRESSION; MUTATIONS; RESISTANCE; ONCOGENE;

D O I：

10.1016/j.cell.2017.01.020

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Investigating therapeutic "outliers'' that show exceptional responses to anti-cancer treatmentcanuncover biomarkers of drug sensitivity. We performed preclinical trials investigating primary murine acute myeloid leukemias (AMLs) generated by retroviral insertional mutagenesis in Kras(G12D) "knockin'' 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 thedominant clone and rendered it sensitive to MEK inhibition. Similarly, human colorectal cancer cell lines with increasedKRASmutant allele frequency were 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 1,168 (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.

引用

页码：817 / +

页数：28

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