TY  - JOUR
A1  - Brammeld, Jonathan S.
A1  - Petljak, Mia
A1  - Martincorena, Inigo
A1  - Williams, Steven P.
A1  - Alonso, Luz Garcia
A1  - Dalmases, Alba
A1  - Bellosillo, Beatriz
A1  - Robles-Espinoza, Carla Daniela
A1  - Price, Stacey
A1  - Barthorpe, Syd
A1  - Tarpey, Patrick
A1  - Alifrangis, Constantine
A1  - Bignell, Graham
A1  - Vidal, Joana
A1  - Young, Jamie
A1  - Stebbings, Lucy
A1  - Beal, Kathryn
A1  - Stratton, Michael R.
A1  - Saez-Rodriguez, Julio
A1  - Garnett, Mathew
A1  - Montagut, Clara
A1  - Iorio, Francesco
A1  - McDermott, Ultan
T1  - Genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutations
Y1  - 2017/02/08 
JF  - Genome Research 
JO  - Genome Research 
DO  - 10.1101/gr.213546.116 
UR  - http://genome.cshlp.org/content/early/2017/03/15/gr.213546.116.abstract 
N2  - Drug resistance is an almost inevitable consequence of cancer therapy and ultimately proves fatal for the majority of patients. In many cases, this is the consequence of specific gene mutations that have the potential to be targeted to resensitize the tumor. The ability to uniformly saturate the genome with point mutations without chromosome or nucleotide sequence context bias would open the door to identify all putative drug resistance mutations in cancer models. Here, we describe such a method for elucidating drug resistance mechanisms using genome-wide chemical mutagenesis allied to next-generation sequencing. We show that chemically mutagenizing the genome of cancer cells dramatically increases the number of drug-resistant clones and allows the detection of both known and novel drug resistance mutations. We used an efficient computational process that allows for the rapid identification of involved pathways and druggable targets. Such a priori knowledge would greatly empower serial monitoring strategies for drug resistance in the clinic as well as the development of trials for drug-resistant patients. 
ER  -