Reference Detail

Ref Type

Journal Article

PMID

(28179366)

Authors

Brammeld JS, Petljak M, Martincorena I, Williams SP, Alonso LG, Dalmases A, Bellosillo B, Robles-Espinoza CD, Price S, Barthorpe S, Tarpey P, Alifrangis C, Bignell G, Vidal J, Young J, Stebbings L, Beal K, Stratton MR, Saez-Rodriguez J, Garnett M, Montagut C, Iorio F, McDermott U

Title

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

Journal	Vol	Issue	Date	Pages	Journal Short Title
Genome research			2017 Feb 08	613-625	Genome Res

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
NRAS G12V	colorectal cancer	resistant	Cetuximab	Preclinical - Cell culture	Actionable	In a preclinical study, colorectal cancer cells harboring NRAS G12V demonstrated resistance to Erbitux (cetuximab) in culture (PMID: 28179366).	28179366
MAP2K1 F53L	colorectal cancer	resistant	Cetuximab	Preclinical - Cell culture	Actionable	In a preclinical study, expression of MAP2K1 F53L conferred resistance to Erbitux (cetuximab) in colorectal cancer cells in culture (PMID: 28179366).	28179366
NRAS G12V	colorectal cancer	sensitive	Cetuximab + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Erbitux (cetuximab) and Mekinist (trametinib) decreased viability of colorectal cancer cells harboring NRAS G12V in culture (PMID: 28179366).	28179366
MAP2K1 C121S	colorectal cancer	resistant	Cetuximab	Preclinical - Cell culture	Actionable	In a preclinical study, expression of MAP2K1 C121S conferred resistance to Erbitux (cetuximab) in colorectal cancer cells in culture (PMID: 28179366).	28179366
MAP2K1 C121S	colorectal cancer	sensitive	Cetuximab + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Erbitux (cetuximab) and Mekinist (trametinib) decreased viability of colorectal cancer cells harboring MAP2K1 C121S in culture (PMID: 28179366).	28179366
MAP2K1 F53L	colorectal cancer	sensitive	Cetuximab + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, the combination of Erbitux (cetuximab) and Mekinist (trametinib) decreased viability of colorectal cancer cells harboring MAP2K1 F53L in culture (PMID: 28179366).	28179366