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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Journal ArticleDOI
ALK Rearrangements Are Mutually Exclusive with Mutations in EGFR or KRAS: An Analysis of 1,683 Patients with Non–Small Cell Lung Cancer
Justin F. Gainor,Anna M. Varghese,Sai-Hong Ignatius Ou,Sheheryar Kabraji,Mark M. Awad,Ryohei Katayama,Amanda C. Pawlak,Mari Mino-Kenudson,Beow Y. Yeap,Gregory J. Riely,A. John Iafrate,Maria E. Arcila,Marc Ladanyi,Jeffrey A. Engelman,Dora Dias-Santagata,Alice T. Shaw +15 more
TL;DR: Functional ALK rearrangements were mutually exclusive with EGFR and KRAS mutations in a large Western patient population, and this lack of overlap was also observed in ALK-positive cancers with acquired resistance to crizotinib.
Journal ArticleDOI
Rearrangements of the RAF Kinase Pathway in Prostate Cancer, Gastric Cancer and Melanoma
Nallasivam Palanisamy,Bushra Ateeq,Shanker Kalyana-Sundaram,Dorothee Pflueger,Dorothee Pflueger,Kalpana Ramnarayanan,Sunita Shankar,Bo Han,Qi Cao,Xuhong Cao,Xuhong Cao,Khalid Suleman,Chandan Kumar-Sinha,Saravana M. Dhanasekaran,Ying-Bei Chen,Raquel Esgueva,Samprit Banerjee,Christopher J. LaFargue,Javed Siddiqui,Francesca Demichelis,Peter Moeller,Tarek A. Bismar,Rainer Kuefer,Douglas R. Fullen,Timothy M. Johnson,Joel K. Greenson,Thomas J. Giordano,Patrick Tan,Scott A. Tomlins,Sooryanarayana Varambally,Mark A. Rubin,Christopher G. Maher,Arul M. Chinnaiyan +32 more
TL;DR: The results emphasize the key role of RAF family gene rearrangements in cancer, suggest that RAF and MEK inhibitors may be useful in a subset of gene fusion–harboring solid tumors and demonstrate that sequencing of tumor transcriptomes and genomes may lead to the identification of rare targetable fusions across cancer types.
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BIM Mediates EGFR Tyrosine Kinase Inhibitor-Induced Apoptosis in Lung Cancers with Oncogenic EGFR Mutations
Daniel B. Costa,Balazs Halmos,Amit Kumar,Susan Schumer,Mark S. Huberman,Titus J. Boggon,Daniel G. Tenen,Susumu Kobayashi +7 more
TL;DR: Evidence is provided that BIM is involved in TKI- induced apoptosis in sensitive EGFR-mutant cells and that both attenuation of the up-regulation of BIM and resistance to gefitinib-induced apoptosis are seen in models that contain the common EGFR T790M and the novel L747S secondary resistance mutations.
Journal ArticleDOI
A transforming KIF5B and RET gene fusion in lung adenocarcinoma revealed from whole-genome and transcriptome sequencing
Young Seok Ju,Won-Chul Lee,Jong Yeon Shin,Seung-Bok Lee,Thomas Bleazard,Jae Kyung Won,Young Tae Kim,Jong Il Kim,Jin Hyoung Kang,Jeong-Sun Seo +9 more
TL;DR: It is demonstrated that a subset of NSCLCs could be caused by a fusion of KIF5B and RET, and suggested the chimeric oncogene as a promising molecular target for the personalized diagnosis and treatment of lung cancer.
Journal ArticleDOI
RET Fusions Define a Unique Molecular and Clinicopathologic Subtype of Non–Small-Cell Lung Cancer
Rui Wang,Haichuan Hu,Yunjian Pan,Yuan Li,Ting Ye,Chenguang Li,Xiaoyang Luo,Lei Wang,Hang Li,Yang Zhang,Fei Li,Yongming Lu,Qiong Lu,Jie Xu,David H. Garfield,Lei Shen,Hongbin Ji,William Pao,Yihua Sun,Haiquan Chen +19 more
TL;DR: The RET fusion gene occurs in 1.4% of NSCLCs and 1.7% of lung adenocarcinomas and has identifiable clinicopathologic characteristics, warranting further clinical consideration and targeted therapy investigation.
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