TY - JOUR
T1 - Rare but recurrent ROS1 fusions resulting from chromosome 6q22 microdeletions are targetable oncogenes in glioma
AU - Davare, Monika A.
AU - Henderson, Jacob J.
AU - Agarwal, Anupriya
AU - Wagner, Jacob P.
AU - Iyer, Sudarshan R.
AU - Shah, Nameeta
AU - Woltjer, Randy
AU - Somwar, Romel
AU - Gilheeney, Stephen W.
AU - DeCarvalo, Ana
AU - Mikkelson, Tom
AU - Van Meir, Erwin G.
AU - Ladanyi, Marc
AU - Druker, Brian J.
N1 - Funding Information:
We would like to thank Rebecca L. Smith (Knight Cancer Institute) for her help with molecular cloning of ROS1-fusions, Dr. Nicolle E. Hofmann for her assistance with U118MG 3D culture, and Madison Wise Nakamoto in the Dr. Jim Olson's laboratory at the Fred Hutchinson Cancer Research Center for teaching us efficient intracranial orthotopic xenograft techniques. This study was supported in part by funding from the Howard Hughes Medical Institute (to B.J. Druker) and Hyundai Hope on Wheels Hope grant (to M.A. Davare)
Funding Information:
We would like to thank Rebecca L. Smith (Knight Cancer Institute) for her help with molecular cloning of ROS1-fusions, Dr. Nicolle E. Hofmann for her assistance with U118MG 3D culture, and Madison Wise Nakamoto in the Dr. Jim Olson's laboratory at the Fred Hutchinson Cancer Research Center for teaching us efficient intracranial orthotopic xenograft techniques. This study was supported in part by funding from the Howard Hughes Medical Institute (to B.J. Druker) and Hyundai Hope on Wheels Hope grant (to M.A. Davare) Thecosts of publication ofthis article were defrayed inpart by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Funding Information:
R. Somwar reports receiving commercial research grants from Helsinn Healthcare. No potential conflicts of interest were disclosed by the other authors.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/12/15
Y1 - 2018/12/15
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-18-1052
DO - 10.1158/1078-0432.CCR-18-1052
M3 - Article
C2 - 30171048
AN - SCOPUS:85058460881
SN - 1078-0432
VL - 24
SP - 6471
EP - 6482
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 24
ER -