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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Non-small-cell lung cancers: a heterogeneous set of diseases
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Safety and Antitumor Activity of the Multitargeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib: Combined Results from Two Phase I Trials (ALKA-372-001 and STARTRK-1).
Alexander Drilon,Salvatore Siena,Sai-Hong Ignatius Ou,Manish Patel,Myung-Ju Ahn,Jeeyun Lee,Todd M. Bauer,Anna F. Farago,Jennifer J. Wheler,Stephen V. Liu,Robert C. Doebele,Laura Giannetta,Giulio Cerea,Giovanna Marrapese,Michele Schirru,Alessio Amatu,Katia Bencardino,Laura Palmeri,Andrea Sartore-Bianchi,Angelo Vanzulli,Sara Cresta,Silvia Damian,Matteo Duca,Elena Ardini,Gang Li,Jason Christiansen,Karey Kowalski,Ann D. Johnson,Rupal Patel,David Luo,Edna Chow-Maneval,Zachary Hornby,Pratik S. Multani,Alice T. Shaw,Filippo de Braud +34 more
TL;DR: Entrectinib was shown to be well tolerated and active against those gene fusions in solid tumors, including in patients with primary or secondary CNS disease, and a complete CNS response was achieved in a patient with SQSTM1-NTRK1-rearranged lung cancer.
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The emerging complexity of gene fusions in cancer
TL;DR: The spectrum of gene fusions in cancer and how the methods to identify them have evolved are described, and the conceptual implications of current, sequencing-based approaches for detection are discussed.
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Erratum: Non-small-cell lung cancers: a heterogeneous set of diseases
TL;DR: ADCs can be modelled by KrasG12D expression (long latency), KrasD expression and Trp53-null, and epidermal growth factor receptor (EGFR)T790M/L858R, among other genetic models, and they are thought to arise from more distal airway cells.
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The landscape and therapeutic relevance of cancer-associated transcript fusions.
Kosuke Yoshihara,Qianghu Wang,Wandaliz Torres-Garcia,Siyuan Zheng,Rahulsimham Vegesna,Hoon Kim,Roel G.W. Verhaak +6 more
TL;DR: The landscape of transcript fusions detected across a large number of tumor samples was described and revealed fusion events with clinical relevance that have not been previously recognized, support the concept of basket clinical trials and reveal an important role for tumorigenesis.
References
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TL;DR: AUY922 had an acceptable safety profile and clinical activity was seen in pts with ALK+ and EGFR-mut NSCLC, with partial responses in 6/21 (29%) pts and 7/35 (20%) pts, respectively, and response and PFS rates suggest further studies are warranted in these patient populations, particularly in EGfr-mut pts who progressed following treatment with TKIs.
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