# 15 Years Old ALK Gene from Birth to Adolescence; Where to in NBL

## TL;DR

This paper reviews the ALK gene's role in neuroblastoma, highlighting its importance in diagnosis, prognosis, and targeted therapies, and suggests future research directions.

## Contribution

The paper provides a comprehensive review of ALK gene alterations in neuroblastoma and suggests future research and clinical strategies.

## Key findings

- ALK aberrations in neuroblastoma have led to the development of ALK inhibitors with clinical efficacy.
- Activating mutations in ALK's kinase domain are linked to poor outcomes and therapy resistance.
- Circulating tumor DNA could enable non-invasive monitoring of ALK-positive neuroblastoma patients.

## Abstract

This review provides a comprehensive understanding of the ALK gene, encompassing its prevalence, genetic alterations, and significance in neuroblastoma diagnosis, outcome prediction, and targeted therapy utilization. The insights presented aim to inform future research directions and clinical practices in this field.

High risk neuroblastoma, comprising approximately 50% of all cases, presents a particularly poor prognosis. In 2008, the discovery of ALK aberrations in neuroblastoma marked a significant breakthrough, leading to the recognition of ALK as a target for tumors with activating ALK alterations. This discovery has paved the way for the development of various ALK inhibitors, which have shown promising clinical efficacy. ALK amplification, often observed alongside MYCN amplification, has been associated with unfavorable outcomes in patients. Activating mutations in the kinase domain of ALK, particularly at hotspot positions F1174, R1275, and F1245, have been identified. These mutations can occur at clonal or subclonal levels, posing challenges for early detection and potentially influencing disease progression and therapy resistance. The availability of ALK inhibitors, initially developed for adult cancers, has expedited the translation of this knowledge into targeted therapies for neuroblastoma. However, resistance to ALK inhibitors can emerge as a result of treatment or preexist as subclones within the tumor prior to therapy.

Future trials should focus on identifying additional targets complementing ALK inhibition to enhance treatment efficacy and overcome acquired resistance. Furthermore, the utilization of circulating tumor DNA as a non-invasive approach for longitudinal monitoring of ALK-positive neuroblastoma patients, in combination with radiographic evaluation of treatment response, holds promise for understanding dynamic tumor changes over time.