Reference Detail

Contact

Missing content? – Request curation!

Request curation for specific Genes, variants, or PubMed publications.

Have questions, comments or suggestions? - Let us know!

Email us at : ckbsupport@jax.org

Ref Type Journal Article
PMID (26582713)
Authors Gannon HS, Kaplan N, Tsherniak A, Vazquez F, Weir BA, Hahn WC, Meyerson M
Title Identification of an "Exceptional Responder" Cell Line to MEK1 Inhibition: Clinical Implications for MEK-Targeted Therapy.
Journal Molecular cancer research : MCR
Vol 14
Issue 2
Date 2016 Feb
URL
Abstract Text The identification of somatic genetic alterations that confer sensitivity to pharmacologic inhibitors has led to new cancer therapies. To identify mutations that confer an exceptional dependency, shRNA-based loss-of-function data were analyzed from a dataset of numerous cell lines to reveal genes that are essential in a small subset of cancer cell lines. Once these cell lines were determined, detailed genomic characterization from these cell lines was utilized to ascertain the genomic aberrations that led to this extreme dependency. This method, in a large subset of lung cancer cell lines, yielded a single lung adenocarcinoma cell line, NCI-H1437, which is sensitive to RNA interference of MAP2K1 expression. Notably, NCI-H1437 is the only lung cancer cell line included in the dataset with a known activating mutation in MAP2K1 (Q56P). Subsequent validation using shRNA and CRISPR-Cas9 confirmed MAP2K1 dependency. In vitro and in vivo inhibitor studies established that NCI-H1437 cells are sensitive to MEK1 inhibitors, including the FDA-approved drug trametinib. Like NCI-H1437 cells, the MAP2K1-mutant cell lines SNU-C1 (colon) and OCUM-1 (gastric) showed decreased viability after MAP2K1 depletion via Cas9-mediated gene editing. Similarly, these cell lines were particularly sensitive to trametinib treatment compared with control cell lines. On the basis of these data, cancers that harbor driver mutations in MAP2K1 could benefit from treatment with MEK1 inhibitors. Furthermore, this functional data mining approach provides a general method to experimentally test genomic features that confer dependence in tumors.Cancers with an activated RAS/MAPK pathway driven by oncogenic MAP2K1 mutations may be particularly sensitive to MEK1 inhibitor treatments.

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 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
MAP2K1 D351G missense unknown MAP2K1 D351G lies within the protein kinase domain of the Map2k1 protein (UniProt.org). D351G has been identified in the scientific literature (PMID: 26582713, PMID: 24755471), but has not been biochemically characterized and therefore, its effect on Map2k1 protein function is unknown (PubMed, Aug 2020).
MAP2K1 S331R missense unknown MAP2K1 S331R lies within the protein kinase domain of the Map2k1 protein (UniProt.org). S331R has been identified in the scientific literature (PMID: 25351745, PMID: 26582713), but has not been biochemically characterized and therefore, its effect on Map2k1 protein function is unknown (PubMed, Aug 2020).
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
MAP2K1 Q56P lung adenocarcinoma sensitive Trametinib Preclinical Actionable In a preclinical study, a lung adenocarcinoma cell line harboring MAP2K1 Q56P demonstrated sensitivity to Mekinist (trametinib), resulting in decreased cell viability (PMID: 26582713). 26582713
MAP2K1 Q56P lung adenocarcinoma sensitive Refametinib Preclinical Actionable In a preclinical study, a lung adenocarcinoma cell line harboring MAP2K1 Q56P demonstrated sensitivity to Refametinib (BAY86-9766), resulting in decreased cell viability (PMID: 26582713). 26582713
MAP2K1 Q56P stomach cancer sensitive Trametinib Preclinical Actionable In a preclinical study, a gastric cancer cell line harboring MAP2K1 Q56P demonstrated sensitivity to Mekinist (trametinib), resulting in decreased cell viability (PMID: 26582713). 26582713
MAP2K1 Q56P lung adenocarcinoma sensitive Selumetinib Preclinical Actionable In a preclinical study, a lung adenocarcinoma cell line harboring MAP2K1 Q56P demonstrated sensitivity to Selumetinib (AZD6244), resulting in decreased cell viability (PMID: 26582713). 26582713
MAP2K1 Q56P lung adenocarcinoma sensitive PD-0325901 Preclinical Actionable In a preclinical study, a lung adenocarcinoma cell line harboring MAP2K1 Q56P demonstrated sensitivity to PD-0325901, resulting in decreased cell viability (PMID: 26582713). 26582713
MAP2K1 F53L colorectal cancer sensitive Trametinib Preclinical Actionable In a preclinical study, a colorectal cancer cell line harboring MAP2K1 F53L demonstrated sensitivity to Mekinist (trametinib) in culture, resulting in decreased cell viability (PMID: 26582713). 26582713