Sustained Response to Entrectinib in an Infant With a Germline ALKAL2 Variant and Refractory Metastatic Neuroblastoma With Chromosomal 2p Gain and Anaplastic Lymphoma Kinase and Tropomyosin Receptor Kinase Activation

摘要

Introduction: Despite improved clinical outcomes from multimodal therapy, long-term survival of children with high-risk neuroblastoma (NB) is only about 50%. Targeted approaches may improve these patients' outcomes. The anaplastic lymphoma kinase (ALK) receptor ty-rosine kinase (RTK) is one of the few oncogenes identified in NB. ALK together with MYCN drives NB in a variety of models. ALK is activated by ALKAL ligands, and ALKAL2 overexpression increases onset and penetrance of 777-MVCN-driven NB in mice. ALKAL2 is located together with ALK and MYCN on distal 2p, a region often gained in NB and linked to poor prognosis. Another RTK involved in NB is tropomyosin receptor kinase (TRK)A. High TRKA expression is a favorable marker, whereas high expression of the related TRKB is a marker of poor prognosis and progression in NB. Alternative splicing adds further complexity: a truncated TRKB isoform is preferentially expressed in differentiating NB, whereas an isoform of TRKA that does not bind nerve growth factor is found in unfavorable NB. Here, we report robust response to RTK inhibition of a patient with NB harboring a rare germline variant in the ALKAL2gene with a chromosomal 2p gain and ALK and TRK activity. On the basis of this case, we suggest that NB patients with 2p gain tumors should be investigated for ALK and other RTK signaling activity when possible, even in the absence of genetic mutations, and considered as candidates for targeted therapy.