Rare but Recurrent ROS1 Fusions Resulting From Chromosome 6q22 Microdeletions are Targetable Oncogenes in Glioma

• Type of Material: Article
• Authors: Monika A. Davare, Oregon Health and Science University; Jacob J. Henderson, Oregon Health and Science University; Anupriya Agarwal, Oregon Health and Science University; Jacob P. Wagner, Oregon Health and Science University; Sudarshan R. Iyer, Oregon Health and Science University; Nameeta Shah, Swedish Neuroscience Institute; Randy Woltjer, Oregon Health and Science University; Romel Somwar, Memorial Sloan Kettering Cancer Center; Stephen W. Gilheeney, Henry Ford Hospital; Ana DeCarvalo, Memorial Sloan Kettering Cancer Center; Tom Mikkelson, Memorial Sloan Kettering Cancer Center; Erwin Van Meir, Emory University; Marc Ladanyi, Memorial Sloan Kettering Cancer Center; Brian J. Druker, Oregon Health and Science University
• Language: English
• Date: 2018-12-15
• Publisher: AMER ASSOC CANCER RESEARCH
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 American Association for Cancer Research.
• Final Published Version (URL): http://dx.doi.org/10.1158/1078-0432.CCR-18-1052
• Title of Journal or Parent Work: CLINICAL CANCER RESEARCH
• Volume: 24
• Issue: 24
• Start Page: 6471
• End Page: 6482
• Grant/Funding Information: This study was supported in part by funding from the Howard Hughes Medical Institute (Brian J. Druker) and Hyundai Hope on Wheels Hope grant (Monika A. Davare)
• Keywords: IDENTIFICATION; TYROSINE KINASE; RESISTANCE; ALK; INHIBITOR; LUNG-CANCER; PF-06463922; Life Sciences & Biomedicine; Oncology; Science & Technology; CRIZOTINIB; GLIOBLASTOMA; EXPRESSION
• Research Categories: Health Sciences, Pathology; Health Sciences, Oncology

Abstract

Purpose: Gliomas, a genetically heterogeneous group of primary central nervous system tumors, continue to pose a significant clinical challenge. Discovery of chromosomal rearrangements involving kinase genes has enabled precision therapy, and improved outcomes in several malignancies. Experimental Design: Positing that similar benefit could be accomplished for patients with brain cancer, we evaluated The Cancer Genome Atlas (TCGA) glioblastoma dataset. Functional validation of the oncogenic potential and inhibitory sensitivity of discovered ROS1 fusions was performed using three independent cell-based model systems, and an in vivo murine xenograft study. Results: In silico analysis revealed previously unreported intrachromosomal 6q22 microdeletions that generate ROS1-fusions from TCGA glioblastoma dataset. ROS1 fusions in primary glioma and ependymoma were independently corroborated from MSK-IMPACT and Foundation Medicine clinical datasets. GOPC–ROS1 is a recurrent ROS1 fusion in primary central nervous system (CNS) tumors. CEP85L–ROS1 and GOPC–ROS1 are transforming oncogenes in cells of astrocytic lineage, and amenable to phar-macologic inhibition with several ROS1 inhibitors even when occurring concurrently with other cancer hotspot aberrations frequently associated with glioblastoma. Oral monotherapy with a brain-permeable ROS1 inhibitor, lorlatinib, significantly prolonged survival in an intracranially xenografted tumor model generated from a ROS1 fusion-positive glioblastoma cell line. Conclusions: Our findings highlight that CNS tumors should be specifically interrogated for these rare intrachromosomal 6q22 microdeletion events that generate actionable ROS1 fusions. ROS1 fusions in primary brain cancer may be amenable for clinical intervention with kinase inhibitors, and this holds the potential of novel treatment paradigms in these treatment-refractory cancer types, particularly in glioblastoma.