Jing Ni1, Shaozhen Xie1, Shakti H Ramkissoon1, Victor Luu1, Yu Sun1, Pratiti Bandopadhayay1, Rameen Beroukhim1, Thomas M Roberts1, Charles D Stiles1, Rosalind A Segal1, Keith L Ligon1, William C Hahn1, Jean J Zhao2. 1. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts (J.N., S.X., V.L., Y.S., P.B., R.B., T.M.R., C.D.S., R.A.S., J.J.Z.); Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts (J.N., S.X., V.L., T.M.R., J.J.Z.); Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts (S.H.R., R.B., K.L.L., W.C.H.); Broad Institute, Boston, Massachusetts (P.B., R.B., W.C.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., K.L.L.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.). 2. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts (J.N., S.X., V.L., Y.S., P.B., R.B., T.M.R., C.D.S., R.A.S., J.J.Z.); Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts (J.N., S.X., V.L., T.M.R., J.J.Z.); Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts (S.H.R., R.B., K.L.L., W.C.H.); Broad Institute, Boston, Massachusetts (P.B., R.B., W.C.H.); Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts (S.H.R., K.L.L.); Department of Pathology, Boston Children's Hospital, Boston, Massachusetts (K.L.L.) jean_zhao@dfci.harvard.edu.
Abstract
BACKGROUND: Astrocytomas are the most common primary human brain tumors. Receptor tyrosine kinases (RTKs), including tyrosine receptor kinase B (TrkB, also known as tropomyosin-related kinase B; encoded by neurotrophic tyrosine kinase receptor type 2 [NTRK2]), are frequently mutated by rearrangement/fusion in high-grade and low-grade astrocytomas. We found that activated TrkB can contribute to the development of astrocytoma and might serve as a therapeutic target in this tumor type. METHODS: To identify RTKs capable of inducing astrocytoma formation, a library of human tyrosine kinases was screened for the ability to transform murine Ink4a-/-/Arf-/- astrocytes. Orthotopic allograft studies were conducted to evaluate the effects of RTKs on the development of astrocytoma. Since TrkB was identified as a driver of astrocytoma formation, the effect of the Trk inhibitors AZD1480 and RXDX-101 was assessed in astrocytoma cells expressing activated TrkB. RNA sequencing, real-time PCR, western blotting, and enzyme-linked immunosorbent assays were conducted to characterize NTRK2 in astrocytomas. RESULTS: Activated TrkB cooperated with Ink4a/Arf loss to induce the formation of astrocytomas through a mechanism mediated by activation of signal transducer and activator of transcription 3 (STAT3). TrkB activation positively correlated with Ccl2 expression. TrkB-induced astrocytomas remained dependent on TrkB signaling for survival, highlighting a role of NTRK2 as an addictive oncogene. Furthermore, the QKI-NTRK2 fusion associated with human astrocytoma transformed Ink4a-/-/Arf-/- astrocytes, and this process was also mediated via STAT3 signaling. CONCLUSIONS: Our findings provide evidence that constitutively activated NTRK2 alleles, notably the human tumor-associated QKI-NTRK2 fusion, can cooperate with Ink4a/Arf loss to drive astrocytoma formation. Therefore, we propose NTRK2 as a potential therapeutic target in the subset of astrocytoma patients defined by QKI-NTRK2 fusion.
BACKGROUND:Astrocytomas are the most common primary humanbrain tumors. Receptor tyrosine kinases (RTKs), including tyrosine receptor kinase B (TrkB, also known as tropomyosin-related kinase B; encoded by neurotrophic tyrosine kinase receptor type 2 [NTRK2]), are frequently mutated by rearrangement/fusion in high-grade and low-grade astrocytomas. We found that activated TrkB can contribute to the development of astrocytoma and might serve as a therapeutic target in this tumor type. METHODS: To identify RTKs capable of inducing astrocytoma formation, a library of human tyrosine kinases was screened for the ability to transform murineInk4a-/-/Arf-/- astrocytes. Orthotopic allograft studies were conducted to evaluate the effects of RTKs on the development of astrocytoma. Since TrkB was identified as a driver of astrocytoma formation, the effect of the Trk inhibitors AZD1480 and RXDX-101 was assessed in astrocytoma cells expressing activated TrkB. RNA sequencing, real-time PCR, western blotting, and enzyme-linked immunosorbent assays were conducted to characterize NTRK2 in astrocytomas. RESULTS: Activated TrkB cooperated with Ink4a/Arf loss to induce the formation of astrocytomas through a mechanism mediated by activation of signal transducer and activator of transcription 3 (STAT3). TrkB activation positively correlated with Ccl2 expression. TrkB-induced astrocytomas remained dependent on TrkB signaling for survival, highlighting a role of NTRK2 as an addictive oncogene. Furthermore, the QKI-NTRK2 fusion associated with humanastrocytoma transformed Ink4a-/-/Arf-/- astrocytes, and this process was also mediated via STAT3 signaling. CONCLUSIONS: Our findings provide evidence that constitutively activated NTRK2 alleles, notably the humantumor-associated QKI-NTRK2 fusion, can cooperate with Ink4a/Arf loss to drive astrocytoma formation. Therefore, we propose NTRK2 as a potential therapeutic target in the subset of astrocytomapatients defined by QKI-NTRK2 fusion.
Authors: S W Morris; M N Kirstein; M B Valentine; K G Dittmer; D N Shapiro; D L Saltman; A T Look Journal: Science Date: 1994-03-04 Impact factor: 47.728
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