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|Ref Type||Journal Article|
|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.|
|Date||2017 07 01|
|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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|NTRK2||NCBI||DEE58|EIEE58|GP145-TrkB|OBHD|trk-B|TRKB||NTRK2, neurotrophic receptor tyrosine kinase 2, is membrane receptor tyrosine kinase that binds neurotrophins, initiating signaling cascades that lead to cell growth and differentiation (PMID: 17008023). Inappropriately regulated NTRK2 may be involved in initiation and metastasis of some cancers (PMID: 17008023) and NTRK2 fusions, with multiple gene partners, have been commonly observed in solid tumors (PMID: 32319699), including glioma (PMID: 28512244, PMID: 24705251), while NTRK2 missense mutations may confer resistance to TRK inhibition (PMID: 21242122).||Unknown|
|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|