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Kinase impact assessment in the landscape of fusion genes that retain kinase domains: a pan-cancer study

Pora Kim, Peilin Jia, Zhongming Zhao
2016 Briefings in Bioinformatics  
Assessing the impact of kinase in gene fusion is essential for both identifying driver fusion genes (FGs) and developing molecular targeted therapies.  ...  Kinase domain retention is a crucial factor in kinase fusion genes (KFGs), but such a systematic investigation has not been done yet.  ...  The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.  ... 
doi:10.1093/bib/bbw127 pmid:28013235 pmcid:PMC5952959 fatcat:zs4vay6bdjfw3dw2oz652z7kii

Human transcription factor and protein kinase gene fusions in human cancer

Kari Salokas, Rigbe G. Weldatsadik, Markku Varjosalo
2020 Scientific Reports  
In this study, identified oncofusions from a fusion detection approach (DEEPEST) were analyzed in detail.  ...  Domain architecture of the fusions and their wild-type interactors suggests that abnormal molecular context of protein domains caused by fusion events may unlock the oncogenic potential of the wild type  ...  Discussion We examined the gene fusion landscape in human cancer (from TCGA datasets).  ... 
doi:10.1038/s41598-020-71040-8 pmid:32843691 fatcat:n5oihhbtifbkfldohro3ipayua

Human Transcription Factor and Protein Kinase Gene Fusions in Human Cancer [article]

Kari Salokas, Rigbe G Weldatsadik, Markku Varjosalo
2020 bioRxiv   pre-print
In this study, the identified oncofusions from a fusion detection approach (DEEPEST) were analyzed in more detail. In total, DEEPEST contains 28863 unique fusions.  ...  The domain architecture of the fusions, as well as of their expected interactors, suggests that abnormal molecular context of intact protein domains brought about by fusion events may unlock the oncogenic  ...  Discussion We examined the gene fusion landscape in human cancer (TCGA datasets).  ... 
doi:10.1101/2020.04.09.033613 fatcat:q72l7vxksjbwpd72vorfmoiogq

Identification of Targetable FGFR Gene Fusions in Diverse Cancers

Yi-Mi Wu, Fengyun Su, Shanker Kalyana-Sundaram, Nickolay Khazanov, Bushra Ateeq, Xuhong Cao, Robert J. Lonigro, Pankaj Vats, Rui Wang, Su-Fang Lin, Ann-Joy Cheng, Lakshmi P. Kunju (+13 others)
2013 Cancer Discovery  
After extending our assessment of FGFR rearrangements across multiple tumor cohorts, we identified additional FGFR fusions with intact kinase domains in lung squamous cell cancer, bladder cancer, thyroid  ...  Because of the combinatorial possibilities of FGFR family fusion to a variety of oligomerization partners, clinical sequencing efforts, which incorporate transcriptome analysis for gene fusions, are poised  ...  preparation, Rachell Stender for animal care, and Dan Hayes for referral of patients to the MI-ONCOSEQ program.  ... 
doi:10.1158/ pmid:23558953 pmcid:PMC3694764 fatcat:fcvtrikn7fbjhlvkuajvnedhwu

Tropomyosin Receptor Kinase Inhibitors for the Treatment of TRK Fusion Cancer

Theodore W Laetsch, David S Hong
2021 Clinical Cancer Research  
The incidence of NTRK gene fusions can range from the majority of cases in certain rare cancers to lower rates in a wide range of more common cancers.  ...  Chromosomal rearrangements of NTRK1-3 resulting in gene fusions (NTRK gene fusions) have been clinically validated as oncogenic drivers in a wide range of human cancers.  ...  Acknowledgements Medical writing support was provided by Jim Heighway of Cancer Communications and  ... 
doi:10.1158/1078-0432.ccr-21-0465 pmid:33893159 fatcat:lrqf4o3hwjd27bhi3ehfafwle4

FN3 Domain Engineering [chapter]

Steven Jacobs, Karyn ONeil
2012 Protein Engineering  
In order to determine which loops of the domain might be best utilized for target binding, they assessed the impact of elongation on the conformational stability of the domain.  ...  The library was also cloned into a GFP fusion vector for assessment of library quality (ie. in frame sequences, no stop codons) and folding.  ...  A broad range of topics are covered by providing a solid foundation in protein engineering and supplies readers with knowledge essential to the design and production of proteins.  ... 
doi:10.5772/29566 fatcat:o7b733w4yzcsvk75ewb2cvkqgm

Identification of an Activating Mutation in the Extracellular Domain of HER2 Conferring Resistance to Pertuzumab

Ying Zhang, Shanshan Wu, Xinlei Zhuang, Gaoqi Weng, Jiansheng Fan, Xiaoyue Yang, Yingchun Xu, Liqiang Pan, Tingjun Hou, Zhan Zhou, Shuqing Chen
2019 OncoTargets and Therapy  
With molecular modelling analysis, we confirmed the possibility that the S310F mutation might disrupt the interaction between pertuzumab and HER2 as a result of a significant change in the critical residue  ...  We found through bioinformatics analysis that S310F, an activating mutation in the HER2 extracellular domain, was the most frequent mutation in HER2.  ...  Acknowledgments Disclosure The authors declare no conflicts of interest.  ... 
doi:10.2147/ott.s232912 pmid:31920346 pmcid:PMC6941612 fatcat:24xwobgiazagnnseksmeqwcsnu

Emerging Role of Genomic Rearrangements in Breast Cancer: Applying Knowledge from Other Cancers

Bhavna S. Paratala, Sonia C. Dolfi, Hossein Khiabanian, Lorna Rodriguez-Rodriguez, Shridar Ganesan, Kim M. Hirshfield
2016 Biomarkers in Cancer  
This review discusses the emerging role of genomic rearrangements in breast cancer, with a particular focus on fusion genes.  ...  Significant advances in our knowledge of cancer genomes are rapidly changing the way we think about tumor biology and the heterogeneity of cancer.  ...  Author Contributions Wrote the first draft of the manuscript: BSP and KMH. Contributed to the writing of the manuscript: BSP, SCD, HK, SG, and KMH.  ... 
doi:10.4137/bic.s34417 pmid:26917980 pmcid:PMC4756769 fatcat:tpvdpn6zdngpxnzgsbtqyzevqe

Comprehensive characterization of 536 patient-derived xenograft models prioritizes candidatesfor targeted treatment

Hua Sun, Song Cao, R. Jay Mashl, Chia-Kuei Mo, Simone Zaccaria, Michael C. Wendl, Sherri R. Davies, Matthew H. Bailey, Tina M. Primeau, Jeremy Hoog, Jacqueline L. Mudd, Dennis A. Dean (+148 others)
2021 Nature Communications  
Toward this goal, we have established the genomic landscapes of 536 patient-derived xenograft (PDX) models across 25 cancer types, together with mutation, copy number, fusion, transcriptomic profiles,  ...  AbstractDevelopment of candidate cancer treatments is a resource-intensive process, with the research community continuing to investigate options beyond static genomic characterization.  ...  The breast cancer PDX models from Washington University in St.  ... 
doi:10.1038/s41467-021-25177-3 pmid:34429404 pmcid:PMC8384880 fatcat:t53uwnhuszbcfhsh734gh4yioy

Discovery and Characterization of Recurrent, Targetable ALK Fusions in Leiomyosarcoma

Lara E. Davis, Kevin D. Nusser, Joanna Przybyl, Janét Pittsenbarger, Nicolle E. Hofmann, Sushama Varma, Sujay Vennam, Maria Debiec-Rychter, Matt van de Rijn, Monika A. Davare
2018 Molecular Cancer Research  
These results provide the first functional 15 validation of a targetable oncogenic kinase fusion as a driver in a subset of leiomyosarcomas. 16 Overall, these findings suggest that some soft tissue sarcomas  ...  may harbor previously unknown 17 kinase gene translocations, and their discovery may propel new therapeutic strategies in this 18 treatment-refractory cancer. 19 20 IMPLICATION 21 A subset of leiomyosarcomas  ...  Chromosomal rearrangements of the ALK gene generate chimeric ALK fusion 58 proteins wherein the rearrangement retains the ALK kinase domain sequence with various in-59 frame 5' partners (4).  ... 
doi:10.1158/1541-7786.mcr-18-1075 pmid:30518629 fatcat:r4y3ajnznrd23b3vxmbuq2mvkq

Personalizing Therapy in Advanced Non–Small Cell Lung Cancer

Timothy Burns, Vasilis Ramfidis, Mark Socinski, Liza Villaruz
2013 Seminars in respiratory and critical care medicine  
The recognition that non-small cell lung cancer (NSCLC) is not a single disease entity, but rather a collection of distinct molecularly driven neoplasms, has permanently shifted the therapeutic landscape  ...  The identification of these oncogenic drivers and the triage of patients to clinical trials evaluating novel targeted therapeutic approaches will increasingly mold a landscape of personalized lung cancer  ...  [95] [96] [97] [98] [99] The KIF5B-RET fusion protein retains the full RET kinase domain and the KIF5B coiled-coil domain, which likely participates in homodimerization leading to aberrant activation  ... 
doi:10.1055/s-0033-1358552 pmid:24258572 pmcid:PMC4836173 fatcat:hvppxhnwijeztbrdyxs5ikrhwi

Discovery of clinically relevant fusions in pediatric cancer

Stephanie LaHaye, James R. Fitch, Kyle J. Voytovich, Adam C. Herman, Benjamin J. Kelly, Grant E. Lammi, Jeremy A. Arbesfeld, Saranga Wijeratne, Samuel J. Franklin, Kathleen M. Schieffer, Natalie Bir, Sean D. McGrath (+24 others)
2021 BMC Genomics  
Background Pediatric cancers typically have a distinct genomic landscape when compared to adult cancers and frequently carry somatic gene fusion events that alter gene expression and drive tumorigenesis  ...  Conclusions The EnFusion pipeline offers a streamlined approach to discover fusions in cancer, at higher levels of sensitivity and accuracy than single algorithm methods.  ...  Acknowledgements We thank the patients and their families for participating in our translational research protocol.  ... 
doi:10.1186/s12864-021-08094-z pmid:34863095 pmcid:PMC8642973 fatcat:4ipztgrokbdv3feprwx3sizh6a

Improved detection of gene fusions by applying statistical methods reveals oncogenic RNA cancer drivers

Roozbeh Dehghannasiri, Donald E. Freeman, Milos Jordanski, Gillian L. Hsieh, Ana Damljanovic, Erik Lehnert, Julia Salzman
2019 Proceedings of the National Academy of Sciences of the United States of America  
The extent to which gene fusions function as drivers of cancer remains a critical open question.  ...  DEEPEST also reveals a high enrichment for fusions involving oncogenes in cancers, including ovarian cancer, which has had minimal treatment advances in recent decades, finding that more than 50% of tumors  ...  We thank Steven Artandi for useful discussions, and members of J.S.'s laboratory for feedback on the manuscript.  ... 
doi:10.1073/pnas.1900391116 pmid:31308241 pmcid:PMC6681709 fatcat:mxzz5q3ihzbhtghuqnkeqjd3su

Landscape of activating cancer mutations in FGFR kinases and their differential responses to inhibitors in clinical use

Harshnira Patani, Tom D. Bunney, Nethaji Thiyagarajan, Richard A. Norman, Derek Ogg, Jason Breed, Paul Ashford, Andrew Potterton, Mina Edwards, Sarah V. Williams, Gary S. Thomson, Camilla S.M. Pang (+5 others)
2016 OncoTarget  
We here apply a direct comparative and comprehensive analysis of FGFR3 kinase domain variants representing the diversity of pointmutations reported in this domain.  ...  Wider assessment of the impact of genetic changes on the activation state and drug responses is needed to better link the genomic data and treatment options.  ...  FUNDING The MK laboratory is supported by Cancer Research UK (A16567) and UCL Impact Studentship, in association with AstraZeneca, to HP. CSMP is supported by a MRC Studentship.  ... 
doi:10.18632/oncotarget.8132 pmid:26992226 pmcid:PMC5029699 fatcat:lzier7rbbbginoo76xdxmqsvvy

TAS-120 overcomes resistance to ATP-competitive FGFR inhibitors in patients with FGFR2 fusion-positive intrahepatic cholangiocarcinoma

Lipika Goyal, Lei Shi, Leah Y. Liu, Ferran Fece de la Cruz, Jochen K. Lennerz, Srivatsan Raghavan, Ignaty Leshchiner, Liudmila Elagina, Giulia Siravegna, Raymond W.S. Ng, Phuong Vu, Krushna C Patra (+30 others)
2019 Cancer Discovery  
FGFR2 gene fusions.  ...  Here, we report that the irreversible pan-FGFR inhibitor TAS-120 demonstrated efficacy in 4 patients with FGFR2 fusion-positive ICC who developed resistance to BGJ398 or Debio 1347.  ...  Additional studies will be required to determine the impact of these kinase domain mutations on FGFR2 fusion protein stability and turnover and also on the kinetics of signaling reactivation upon inhibitor  ... 
doi:10.1158/ pmid:31109923 pmcid:PMC6677584 fatcat:ie5ppg3p2ngavnyqr5scjyqpmi
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