PT  - JOURNAL ARTICLE
AU  - Jonathan S. Brammeld
AU  - Mia Petljak
AU  - Inigo Martincorena
AU  - Steven P. Williams
AU  - Luz Garcia Alonso
AU  - Alba Dalmases
AU  - Beatriz Bellosillo
AU  - Carla Daniela Robles-Espinoza
AU  - Stacey Price
AU  - Syd Barthorpe
AU  - Patrick Tarpey
AU  - Constantine Alifrangis
AU  - Graham Bignell
AU  - Joana Vidal
AU  - Jamie Young
AU  - Lucy Stebbings
AU  - Kathryn Beal
AU  - Michael R Stratton
AU  - Julio Saez-Rodriguez
AU  - Mathew Garnett
AU  - Clara Montagut
AU  - Francesco Iorio
AU  - Ultan McDermott
TI  - Genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutations
AID  - 10.1101/066555
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 066555
4099  - http://biorxiv.org/content/early/2017/01/16/066555.short
4100  - http://biorxiv.org/content/early/2017/01/16/066555.full
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.