TY - JOUR
T1 - ALK Amplification and Rearrangements Are Recurrent Targetable Events in Congenital and Adult Glioblastoma
AU - Blandin, Anne Florence
AU - Giglio, Ross
AU - Graham, Maya Srikanth
AU - Garcia, Guadalupe
AU - Malinowski, Seth
AU - Woods, Jared K.
AU - Ramkissoon, Shakti
AU - Ramkissoon, Lori
AU - Dubois, Frank
AU - Schoolcraft, Kathleen
AU - Tsai, Jessica
AU - Wang, Dayle
AU - Jones, Robert
AU - Vogelzang, Jayne
AU - Pelton, Kristine
AU - Becker, Sarah
AU - Watkinson, Fiona
AU - Sinai, Claire
AU - Cohen, Elizabeth F.
AU - Booker, Matthew A.
AU - Tolstorukov, Michael Y.
AU - Haemels, Veerle
AU - Goumnerova, Liliana
AU - Wright, Karen
AU - Kieran, Mark
AU - Fehnel, Katie
AU - Reardon, David
AU - Tauziede-Espariat, Arnault
AU - Lulla, Rishi
AU - Carcamo, Benjamin
AU - Chaleff, Stanley
AU - Charest, Alain
AU - De Smet, Frederik
AU - Ligon, Azra H.
AU - Dubuc, Adrian
AU - Pages, Melanie
AU - Varlet, Pascale
AU - Wen, Patrick Y.
AU - Alexander, Brian M.
AU - Chi, Susan
AU - Alexandrescu, Sanda
AU - Kittler, Ralf
AU - Bachoo, Robert
AU - Bandopadhayay, Pratiti
AU - Beroukhim, Rameen
AU - Ligon, Keith L.
N1 - Publisher Copyright:
© 2023 American Association for Cancer Research.
PY - 2023/7
Y1 - 2023/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85164845761&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85164845761&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-21-3521
DO - 10.1158/1078-0432.CCR-21-3521
M3 - Article
C2 - 36780194
AN - SCOPUS:85164845761
SN - 1078-0432
VL - 29
SP - 2651
EP - 2667
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 14
ER -