Molecular Pathways: ROS1 Fusion Proteins in Cancer
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TLDR
Targeting ROS1 fusion proteins with the small-molecule inhibitor crizotinib is showing promise as an effective therapy in patients with NSCLC whose tumors are positive for these genetic abnormalities.Abstract:
Genetic alterations that lead to constitutive activation of kinases are frequently observed in cancer. In many cases, the growth and survival of tumor cells rely upon an activated kinase such that inhibition of its activity is an effective anticancer therapy. ROS1 is a receptor tyrosine kinase that has recently been shown to undergo genetic rearrangements in a variety of human cancers, including glioblastoma, non-small cell lung cancer (NSCLC), cholangiocarcinoma, ovarian cancer, gastric adenocarcinoma, colorectal cancer, inflammatory myofibroblastic tumor, angiosarcoma, and epithelioid hemangioendothelioma. These rearrangements create fusion proteins in which the kinase domain of ROS1 becomes constitutively active and drives cellular proliferation. Targeting ROS1 fusion proteins with the small-molecule inhibitor crizotinib is showing promise as an effective therapy in patients with NSCLC whose tumors are positive for these genetic abnormalities. This review discusses the recent preclinical and clinical findings on ROS1 gene fusions in cancer.read more
Citations
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Journal ArticleDOI
Crizotinib in ROS1-Rearranged Non–Small-Cell Lung Cancer
Alice T. Shaw,Sai-Hong Ignatius Ou,Yung-Jue Bang,D. Ross Camidge,Benjamin Solomon,Ravi Salgia,Gregory J. Riely,Marileila Varella-Garcia,Geoffrey I. Shapiro,Daniel B. Costa,Robert C. Doebele,Long P. Le,Zongli Zheng,Zongli Zheng,Weiwei Tan,Patricia Stephenson,S. Martin Shreeve,L. Tye,James G. Christensen,Keith D. Wilner,Jeffrey W. Clark,A. John Iafrate +21 more
TL;DR: Crizotinib showed marked antitumor activity in patients with advanced ROS1-rearranged NSCLC, and ROS1 rearrangement defines a second molecular subgroup of NSCLCs for which crizotin ib is highly active.
Journal ArticleDOI
Targeted therapy for non-small cell lung cancer: current standards and the promise of the future
Bryan A. Chan,Brett G.M. Hughes +1 more
TL;DR: The major subtypes of oncogenic drivers behind NSCLC are examined as well as the development of targeted agents available to treat them both now and in the foreseeable future.
Journal ArticleDOI
Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer.
Aria Vaishnavi,Marzia Capelletti,Anh T. Le,Severine Kako,Mohit Butaney,Dalia Ercan,Sakshi Mahale,Kurtis D. Davies,Dara L. Aisner,Dara L. Aisner,Amanda B. Pilling,Eamon M. Berge,Jhingook Kim,Hidefumi Sasaki,Seung-Il Park,Gregory V. Kryukov,Levi A. Garraway,Levi A. Garraway,Peter S. Hammerman,Julia Haas,Steven W. Andrews,Doron Lipson,Philip J. Stephens,V.A. Miller,Marileila Varella-Garcia,Marileila Varella-Garcia,Pasi A. Jänne,Robert C. Doebele,Robert C. Doebele +28 more
TL;DR: Tumor samples from 3 of 91 patients with lung cancer without known oncogenic alterations assayed by next-generation sequencing or fluorescence in situ hybridization demonstrated evidence of NTRK1 gene fusions.
Journal ArticleDOI
An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101
Robert C. Doebele,Lara E. Davis,Aria Vaishnavi,Anh T. Le,Adriana Estrada-Bernal,Stephen B. Keysar,Antonio Jimeno,Marileila Varella-Garcia,Dara L. Aisner,Yali Li,Philip J. Stephens,Deborah Morosini,Brian B. Tuch,Michele Fernandes,Nisha Nanda,Jennifer A. Low +15 more
TL;DR: A patient with a metastatic soft-tissue sarcoma with an LMNA-NTRK1 fusion had rapid and substantial tumor regression with a novel, highly selective TRK inhibitor, LOXO-101, providing the first clinical evidence of benefit from inhibiting TRK fusions.
Journal ArticleDOI
Inflammatory Myofibroblastic Tumors Harbor Multiple Potentially Actionable Kinase Fusions
Christine M. Lovly,Abha A. Gupta,Doron Lipson,Geoff Otto,Tina Brennan,Catherine T. Chung,Scott C. Borinstein,Jeffrey S. Ross,Philip J. Stephens,Vincent A. Miller,Cheryl M. Coffin +10 more
TL;DR: This study describes the most comprehensive genomics-based evaluation of IMT to date, and reports for the first time that IMTs harbor other actionable targets, including ROS1 and PDGFRβ fusions.
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TL;DR: ROS1 rearrangement defines a molecular subset of NSCLC with distinct clinical characteristics that are similar to those observed in patients with ALK-rearranged NSCLCs, and crizotinib shows in vitro activity and early evidence of clinical activity in ROS1- rearrangedNSCLC.
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Kengo Takeuchi,Manabu Soda,Yuki Togashi,Ritsuro Suzuki,Seiji Sakata,Satoko Hatano,Reimi Asaka,Wakako Hamanaka,Hironori Ninomiya,Hirofumi Uehara,Young Lim Choi,Yukitoshi Satoh,Yukitoshi Satoh,Sakae Okumura,Ken Nakagawa,Hiroyuki Mano,Hiroyuki Mano,Yuichi Ishikawa +17 more
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Journal ArticleDOI
Activity and safety of crizotinib in patients with ALK-positive non-small-cell lung cancer: updated results from a phase 1 study.
D. Ross Camidge,Yung-Jue Bang,Eunice L. Kwak,A. John Iafrate,Marileila Varella-Garcia,Stephen B. Fox,Gregory J. Riely,Benjamin Solomon,Sai-Hong Ignatius Ou,Dong Wan Kim,Ravi Salgia,Panagiotis Fidias,Jeffrey A. Engelman,Leena Gandhi,Pasi A. Jänne,Daniel B. Costa,Geoffrey I. Shapiro,Patricia LoRusso,Katherine Ruffner,Patricia Stephenson,Yiyun Tang,Keith D. Wilner,Jeffrey W. Clark,Alice T. Shaw +23 more
TL;DR: Crizotinib is well tolerated with rapid, durable responses in patients with ALK-positive NSCLC and there seems to be potential for ongoing benefit after initial disease progression in this population, but a more formal definition of ongoing benefit in this context is needed.
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