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 Genome research
Vol
Issue
Date 2017 Feb 08
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.

Filtering

  • Case insensitive filtering will display rows where any text in any cell matches the filter term
  • Simple literal full or partial string matches
  • Separate multiple filter terms with a spaces, order doesn't matter (a b c and c b a are equivalent )
  • Filtering will only apply to rows that are already loaded on the page, filtering has no impact on query parameters
  • Use quotes to match a longer phrase which contains spaces "mtor c1483f"

Sorting

  • Generally, the default sort order for tables is set to be first column ascending, however, specific tables may set a different default sort order.
  • Click on any column header arrows to sort by that column
  • Hold down the Shift key and click multiple columns to sort by more than one column, be sure to set ascending or descending order for a given column, before moving on to the next column.

Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Therapy Description
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
R912L missense unknown RET R912L lies within the protein kinase domain of the Ret protein (UniProt.org). R912L has been identified in sequencing studies (PMID: 28179366), but has not been biochemically characterized and therefore, its effect on Ret protein function is unknown (PubMed, Dec 2018).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
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 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
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 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 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 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
KRAS G12C 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 KRAS G12C in culture (PMID: 28179366). 28179366