Molecular pathways: ROS1 fusion proteins in cancer

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.

Figure 1. Schematic of ROS1 fusion proteins and activation of downstream signaling pathways

FIG-ROS1 fusions have been found to be localized to the Golgi apparatus, whereas other ROS1 fusion variants have been reported to be plasma membrane-associated or cytosolic. ROS1 fusion proteins activate growth and survival signaling pathways common to other receptor tyrosine kinases. ESYT1 activation may be a fusion variant-specific downstream signaling component that influences invasion and metastasis.