Reference Detail

Ref Type

Journal Article

PMID

(28512244)

Authors

Lu H, Villafane N, Dogruluk T, Grzeskowiak CL, Kong K, Tsang YH, Zagorodna O, Pantazi A, Yang L, Neill NJ, Kim YW, Creighton CJ, Verhaak RG, Mills GB, Park PJ, Kucherlapati R, Scott KL

Title

Engineering and Functional Characterization of Fusion Genes Identifies Novel Oncogenic Drivers of Cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cancer research	77	13	2017 07 01	3502-3512	Cancer Res

URL

Abstract Text

Oncogenic gene fusions drive many human cancers, but tools to more quickly unravel their functional contributions are needed. Here we describe methodology permitting fusion gene construction for functional evaluation. Using this strategy, we engineered the known fusion oncogenes, BCR-ABL1, EML4-ALK, and ETV6-NTRK3, as well as 20 previously uncharacterized fusion genes identified in The Cancer Genome Atlas datasets. In addition to confirming oncogenic activity of the known fusion oncogenes engineered by our construction strategy, we validated five novel fusion genes involving MET, NTRK2, and BRAF kinases that exhibited potent transforming activity and conferred sensitivity to FDA-approved kinase inhibitors. Our fusion construction strategy also enabled domain-function studies of BRAF fusion genes. Our results confirmed other reports that the transforming activity of BRAF fusions results from truncation-mediated loss of inhibitory domains within the N-terminus of the BRAF protein. BRAF mutations residing within this inhibitory region may provide a means for BRAF activation in cancer, therefore we leveraged the modular design of our fusion gene construction methodology to screen N-terminal domain mutations discovered in tumors that are wild-type at the BRAF mutation hotspot, V600. We identified an oncogenic mutation, F247L, whose expression robustly activated the MAPK pathway and sensitized cells to BRAF and MEK inhibitors. When applied broadly, these tools will facilitate rapid fusion gene construction for subsequent functional characterization and translation into personalized treatment strategies. Cancer Res; 77(13); 3502-12. ©2017 AACR.

Filtering

Case insensitive filtering will display rows if any text in any cell matches the filter term
Use simple literal full or partial string matches
Separate multiple filter terms with a space. Any order may be used (i. e. 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 on a longer phrase with spaces (i.e. "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
BRAF	F247L	missense	gain of function	BRAF F247L lies within the phorbol-ester/DAG-type zinc finger domain of the Braf protein (UniProt.org). F247L confers a gain of function to Braf, as indicated by activation of downstream MAPK signaling and is transforming in cultured cells (PMID: 28512244, PMID: 29533785).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF F247L	Advanced Solid Tumor	sensitive	Dabrafenib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing BRAF F247L demonstrated sensitivity to Tafinlar (dabrafenib) in culture (PMID: 28512244).	28512244
BRAF F247L	Advanced Solid Tumor	sensitive	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing BRAF F247L demonstrated sensitivity to Mekinist (trametinib) in culture (PMID: 28512244).	28512244