Molecular Pathways: ROS1 Fusion Proteins in Cancer

• Published in: Clinical cancer research Vol. 19; no. 15; pp. 4040 - 4045
• Main Authors: DAVIES, Kurtis D, DOEBELE, Robert C
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.08.2013
• Subjects: Antineoplastic agents; Biological and medical sciences; Cell Proliferation; Crizotinib; Humans; Medical sciences; Molecular Targeted Therapy; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Mutation; Neoplasms - drug therapy; Neoplasms - genetics; Neoplasms - pathology; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Pharmacology. Drug treatments; Protein Kinase Inhibitors - therapeutic use; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Pyrazoles - therapeutic use; Pyridines - therapeutic use; Tumors; Fusion protein; Malignant tumor; Cancer
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-12-2851

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.