Tyrosine kinase gene rearrangements in epithelial malignancies
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TLDR
The clinical outcomes with targeted therapies, aetiologic, pathogenic and clinical features that are associated with cancers harbouring oncogenic fusion kinases, including anaplastic lymphoma kinase (ALK), ROS1 and RET are examined.Abstract:
In this Review, the authors examine the aetiological, pathogenic and clinical features that are associated with cancers harbouring oncogenic fusion kinases, the clinical outcomes with targeted therapies, and strategies to discover additional kinases that are activated by chromosomal rearrangements in solid tumours. Chromosomal rearrangements that lead to oncogenic kinase activation are observed in many epithelial cancers. These cancers express activated fusion kinases that drive the initiation and progression of malignancy, and often have a considerable response to small-molecule kinase inhibitors, which validates these fusion kinases as 'druggable' targets. In this Review, we examine the aetiologic, pathogenic and clinical features that are associated with cancers harbouring oncogenic fusion kinases, including anaplastic lymphoma kinase (ALK), ROS1 and RET. We discuss the clinical outcomes with targeted therapies and explore strategies to discover additional kinases that are activated by chromosomal rearrangements in solid tumours.read more
Citations
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Convergent mutations and kinase fusions lead to oncogenic STAT3 activation in anaplastic large cell lymphoma.
Ramona Crescenzo,Ramona Crescenzo,Francesco Abate,Francesco Abate,Francesco Abate,Elena Lasorsa,Fabrizio Tabbò,Fabrizio Tabbò,Marcello Gaudiano,Marcello Gaudiano,Nicoletta Chiesa,Filomena Di Giacomo,Elisa Spaccarotella,Luigi Barbarossa,Elisabetta Ercole,Maria Todaro,Maria Todaro,Michela Boi,Michela Boi,Andrea Acquaviva,Elisa Ficarra,Domenico Novero,Andrea Rinaldi,Thomas Tousseyn,Andreas Rosenwald,Lukas Kenner,Lorenzo Cerroni,Alexander Tzankov,Maurilio Ponzoni,Marco Paulli,Dennis D. Weisenburger,Wing C. Chan,Javeed Iqbal,Miguel A. Piris,Alberto Zamò,Carmela Ciardullo,Davide Rossi,Gianluca Gaidano,Stefano Pileri,Stefano Pileri,Enrico Tiacci,Brunangelo Falini,Leonard D. Shultz,Laurence Mevellec,Jorge Vialard,Roberto Piva,Roberto Piva,Francesco Bertoni,Raul Rabadan,Giorgio Inghirami,Giorgio Inghirami,Giorgio Inghirami +51 more
TL;DR: By integrating massive sequencing strategies, this work provides a comprehensive characterization of driver genetic alterations (somatic point mutations, copy number alterations, and gene fusions) in ALK(-) ALCLs and identifies activating mutations of JAK1 and/or STAT3 genes that led to constitutive activation of the JAK/STAT3 pathway.
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Cell death-based treatment of lung adenocarcinoma
TL;DR: Recent advances in understanding the molecular pathways driving tumor progression and related targeted therapies in lung ADCs are discussed and the cell death mechanisms induced by different treatment strategies and their contribution to therapy resistance are analyzed.
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The emerging clinical relevance of genomics in cancer medicine.
TL;DR: The authors describe the emerging clinical relevance of genomics in oncology, in addition to the many challenges that currently preclude routine clinical use, including the need to promote equal access to genomic testing.
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Repotrectinib (TPX-0005) Is a Next-Generation ROS1/TRK/ALK Inhibitor That Potently Inhibits ROS1/TRK/ALK Solvent- Front Mutations
Alexander Drilon,Sai-Hong Ignatius Ou,Byoung Chul Cho,Dong Wan Kim,Jeeyun Lee,Jessica J. Lin,Viola W. Zhu,Myung-Ju Ahn,D. Ross Camidge,Judy Nguyen,Dayong Zhai,Wei Deng,Zhongdong Huang,Evan Rogers,Juliet Liu,Jeff Whitten,John K.C. Lim,Shanna Stopatschinskaja,David M. Hyman,Robert C. Doebele,J. Jean Cui,Alice T. Shaw +21 more
TL;DR: Repotrectinib (TPX-0005) is a rationally designed, low-molecular-weight, macrocyclic TKI that is selective and highly potent against ROS1, TRKA-C, and ALK and may represent an effective therapeutic option for patients with ROS1-, NTRK1-3-, or ALK-rearranged malignancies who have progressed on earlier-generation TKIs.
Journal ArticleDOI
Entrectinib in ROS1 fusion-positive non-small-cell lung cancer: integrated analysis of three phase 1-2 trials.
Alexander Drilon,Alexander Drilon,Salvatore Siena,Rafal Dziadziuszko,Fabrice Barlesi,Matthew G Krebs,Alice T. Shaw,Filippo de Braud,Christian Rolfo,Myung-Ju Ahn,Jürgen Wolf,Takashi Seto,Byoung Chul Cho,Manish R. Patel,Chao Hua Chiu,Thomas John,Koichi Goto,Christos S. Karapetis,Hendrick Tobias Arkenau,Sang We Kim,Yuichiro Ohe,Yu Chung Li,Young Kwang Chae,Christine H. Chung,Gregory A. Otterson,Haruyasu Murakami,Chia-Chi Lin,Daniel Shao-Weng Tan,Hans Prenen,Todd Riehl,Edna Chow-Maneval,B. Simmons,Na Cui,Ann D. Johnson,Susan Eng,Timothy R. Wilson,Robert C. Doebele +36 more
TL;DR: Entrectinib is active with durable disease control in patients with ROS1 fusion-positive NSCLC, and is well tolerated with a manageable safety profile, making it amenable to long-term dosing in these patients.
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Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer
Alice T. Shaw,Dong Wan Kim,Kazuhiko Nakagawa,Takashi Seto,Lucio Crinò,Myung-Ju Ahn,Tommaso De Pas,Benjamin Besse,Benjamin Solomon,Fiona H Blackhall,Yi-Long Wu,Michael Thomas,Kenneth J. O'Byrne,Denis Moro-Sibilot,D. Ross Camidge,Tony Mok,Vera Hirsh,Gregory J. Riely,Shrividya Iyer,V. Tassell,Anna Polli,Keith D. Wilner,Pasi A. Jänne +22 more
TL;DR: Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non-small-cell lung cancer with ALK rearrangement and greater improvement in global quality of life with crizotinIB than with chemotherapy.
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