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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Genomic insights into head and neck cancer
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A secondary RET mutation in the activation loop conferring resistance to vandetanib.
Takashi Nakaoku,Takashi Kohno,Mitsugu Araki,Seiji Niho,Rakhee Chauhan,Phillip P. Knowles,Katsuya Tsuchihara,Shingo Matsumoto,Yoko Shimada,Sachiyo Mimaki,Genichiro Ishii,Hitoshi Ichikawa,Satoru Nagatoishi,Kouhei Tsumoto,Yasushi Okuno,Kiyotaka Yoh,Neil Q. McDonald,Neil Q. McDonald,Koichi Goto +18 more
TL;DR: It is reported in a lung adenocarcinoma patient harboring a CCDC6-RET mutation in the RET kinase (S904F) that results in resistance to the kinase inhibitor vandetanib by increasing the ATP affinity and autophosphorylation activity ofRET kinase.
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Clinical targeting of mutated and wild-type protein tyrosine kinases in cancer.
TL;DR: Evidence supporting the common mechanisms of protein tyrosine kinase activation in cancer is summarized and a personal perspective on the kinases BCR-ABL and BTK, as well as nonmutated kinase targets in prostate cancer, are provided.
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ALK Fusion Partners Impact Response to ALK Inhibition: Differential Effects on Sensitivity, Cellular Phenotypes, and Biochemical Properties
Merrida A Childress,Stephen M. Himmelberg,Huiqin Chen,Wanleng Deng,Michael A. Davies,Christine M. Lovly,Christine M. Lovly +6 more
TL;DR: Results demonstrate that the 5′ ALK fusion partner plays an important biological role that affects sensitivity to ALK TKIs, and has ramifications for other kinase-driven malignancies.
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ROS1 fusions in cancer: a review
Arnaud Uguen,Marc De Braekeleer +1 more
TL;DR: Different ROS1 fusions have distinct subcellular localization, suggesting that they may activate different substrates in vivo.
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TL;DR: It is shown that a small inversion within chromosome 2p results in the formation of a fusion gene comprising portions of the echinoderm microtubule-associated protein-like 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene in non-small-cell lung cancer (NSCLC) cells.
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Anaplastic Lymphoma Kinase Inhibition in Non–Small-Cell Lung Cancer
Eunice L. Kwak,Yung-Jue Bang,D. Ross Camidge,Alice T. Shaw,Benjamin Solomon,Robert G. Maki,Sai-Hong Ignatius Ou,Bruce J. Dezube,Pasi A. Jänne,Daniel B. Costa,Marileila Varella-Garcia,Woo-Ho Kim,Thomas J. Lynch,Panos Fidias,Hannah Stubbs,Jeffrey A. Engelman,Lecia V. Sequist,Weiwei Tan,Leena Gandhi,Mari Mino-Kenudson,Greg C. Wei,S. Martin Shreeve,Mark J. Ratain,Jeffrey Settleman,James G. Christensen,Daniel A. Haber,Keith D. Wilner,Ravi Salgia,Geoffrey I. Shapiro,Jeffrey W. Clark,A. John Iafrate +30 more
TL;DR: The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients, and the drug resulted in grade 1 or 2 gastrointestinal side effects.
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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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