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Genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutations.

By Jonathan S. Brammeld, Mia Petljak, Inigo Martincorena, Steven P. Williams, Luz Garcia Alonso, Alba Dalmases, Beatriz Bellosillo, Carla Daniela Robles-Espinoza, Stacey Price, Syd Barthorpe, Patrick Tarpey, Constantine Alifrangis, Graham Bignell, Joana Vidal, Jamie Young, Lucy Stebbings, Kathryn Beal, Michael R. Stratton, Julio Saez-Rodriguez, Mathew Garnett, Clara Montagut, Francesco Iorio, Ultan McDermott

Posted 28 Jul 2016
bioRxiv DOI: 10.1101/066555 (published DOI: 10.1101/gr.213546.116)

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.

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