TY - JOUR T1 - Genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutations JF - bioRxiv DO - 10.1101/066555 SP - 066555 AU - Jonathan Brammeld AU - Mia Petljak 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 Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/07/28/066555.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 and re-sensitize the tumor. The means therefore to saturate the genome with point mutations and that avoids chromosome or nucleotide sequence context bias would open the door to identify all possible 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. ER -