ALK Amplification and Rearrangements Are Recurrent Targetable Events in Congenital and Adult Glioblastoma

Area of Science:

• Neuro-oncology
• Genetics
• Molecular Biology

Background:

• Anaplastic lymphoma kinase (ALK) aberrations are implicated in pediatric-type infant gliomas, but their prevalence and impact across diverse age groups remain unclear.
• Understanding ALK aberration frequency, functional consequences, and therapeutic responses in gliomas is crucial for developing targeted treatments.

Discussion:

• ALK aberrations, including novel fusions, were identified in 12% of gliomas spanning 0-80 years, with higher prevalence in congenital/infant cases.
• ALK rearrangements activate STAT3 and ERK1/2 pathways, driving transformation in vitro and in vivo, and gliomas with ALK fusions respond to ALK inhibitors.
• While ALK inhibitors showed no adverse effects on perinatal brain development in mice, ALK protein expression is minimal in the perinatal forebrain.

Key Insights:

• ALK aberrations are a significant driver in a subset of infant and adult glioblastomas.
• ALK-fusions are the sole drivers in infant gliomas, whereas they co-occur with other drivers in adults.
• ALK-fused glioblastoma models demonstrate sensitivity to ALK inhibitors.

Outlook:

• Brain-penetrant ALK inhibitors represent a promising therapeutic strategy for clinical trials in infant, pediatric, and adult gliomas.
• Further research into ALK aberration mechanisms and inhibitor efficacy across different glioma subtypes is warranted.