RT Journal Article
SR Electronic
T1 Genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutations
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 066555
DO 10.1101/066555
A1 Jonathan S. Brammeld
A1 Mia Petljak
A1 Inigo Martincorena
A1 Steven P. Williams
A1 Luz Garcia Alonso
A1 Alba Dalmases
A1 Beatriz Bellosillo
A1 Carla Daniela Robles-Espinoza
A1 Stacey Price
A1 Syd Barthorpe
A1 Patrick Tarpey
A1 Constantine Alifrangis
A1 Graham Bignell
A1 Joana Vidal
A1 Jamie Young
A1 Lucy Stebbings
A1 Kathryn Beal
A1 Michael R Stratton
A1 Julio Saez-Rodriguez
A1 Mathew Garnett
A1 Clara Montagut
A1 Francesco Iorio
A1 Ultan McDermott
YR 2017
UL http://biorxiv.org/content/early/2017/01/16/066555.abstract
AB 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 re-sensitize 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 have developed 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.