KRAS allelic imbalance enhances fitness and modulates MAP kinase dependence in cancer Journal Article

   

Authors:	Burgess, M. R.; Hwang, E.; Mroue, R.; Bielski, C. M.; Wandler, A. M.; Huang, B. J.; Firestone, A. J.; Young, A.; Lacap, J. A.; Crocker, L.; Asthana, S.; Davis, E. M.; Xu, J.; Akagi, K.; Le Beau, M. M.; Li, Q.; Haley, B.; Stokoe, D.; Sampath, D.; Taylor, B. S.; Evangelista, M.; Shannon, K.
Article Title:	KRAS allelic imbalance enhances fitness and modulates MAP kinase dependence in cancer
Abstract:	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 “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 the dominant clone and rendered it sensitive to MEK inhibition. Similarly, human colorectal cancer cell lines with increased KRAS mutant 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. © 2017 Elsevier Inc.
Keywords:	colorectal cancer; drug resistance; kras; aml; mek inhibition; allelic imbalance
Journal Title:	Cell
Volume:	168
Issue:	5
ISSN:	0092-8674
Publisher:	Cell Press
Date Published:	2017-02-23
Start Page:	817
End Page:	829.e15
Language:	English
DOI:	10.1016/j.cell.2017.01.020
PROVIDER:	scopus
PUBMED:	28215705
PMCID:	PMC5541948
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85012927459&doi=10.1016%2fj.cell.2017.01.020&partnerID=40&md5=64376176f9cb1359480666bf50c170c3
Notes:	Article -- Export Date: 4 April 2017 -- Source: Scopus

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