| Autor: |
Keith L. Ligon, Rameen Beroukhim, Pratiti Bandopadhayay, Robert Bachoo, Ralf Kittler, Sanda Alexandrescu, Susan Chi, Brian M. Alexander, Patrick Y. Wen, Pascale Varlet, Melanie Pages, Adrian Dubuc, Azra H. Ligon, Frederik De Smet, Alain Charest, Stanley Chaleff, Benjamin Carcamo, Rishi Lulla, Arnault Tauziede-Espariat, David Reardon, Katie Fehnel, Mark Kieran, Karen Wright, Liliana Goumnerova, Veerle Haemels, Michael Y. Tolstorukov, Matthew A. Booker, Elizabeth F. Cohen, Claire Sinai, Fiona Watkinson, Sarah Becker, Kristine Pelton, Jayne Vogelzang, Robert Jones, Dayle Wang, Jessica Tsai, Kathleen Schoolcraft, Frank Dubois, Lori Ramkissoon, Shakti Ramkissoon, Jared K. Woods, Seth Malinowski, Guadalupe Garcia, Maya Srikanth Graham, Ross Giglio, Anne-Florence Blandin |
| Rok vydání: |
2023 |
| Popis: |
Purpose:Anaplastic lymphoma kinase (ALK) aberrations have been identified in pediatric-type infant gliomas, but their occurrence across age groups, functional effects, and treatment response has not been broadly established.Experimental Design:We performed a comprehensive analysis of ALK expression and genomic aberrations in both newly generated and retrospective data from 371 glioblastomas (156 adult, 205 infant/pediatric, and 10 congenital) with in vitro and in vivo validation of aberrations.Results:ALK aberrations at the protein or genomic level were detected in 12% of gliomas (45/371) in a wide age range (0–80 years). Recurrent as well as novel ALK fusions (LRRFIP1–ALK, DCTN1–ALK, PRKD3–ALK) were present in 50% (5/10) of congenital/infant, 1.4% (3/205) of pediatric, and 1.9% (3/156) of adult GBMs. ALK fusions were present as the only candidate driver in congenital/infant GBMs and were sometimes focally amplified. In contrast, adult ALK fusions co-occurred with other oncogenic drivers. No activating ALK mutations were identified in any age group. Novel and recurrent ALK rearrangements promoted STAT3 and ERK1/2 pathways and transformation in vitro and in vivo. ALK-fused GBM cellular and mouse models were responsive to ALK inhibitors, including in patient cells derived from a congenital GBM. Relevant to the treatment of infant gliomas, we showed that ALK protein appears minimally expressed in the forebrain at perinatal stages, and no gross effects on perinatal brain development were seen in pregnant mice treated with the ALK inhibitor ceritinib.Conclusions:These findings support use of brain-penetrant ALK inhibitors in clinical trials across infant, pediatric, and adult GBMs. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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