Targeted therapy for pediatric central nervous system tumors harboring mutagenic tropomyosin receptor kinases

Area of Science:

• Oncology
• Genetics
• Pharmacology

Background:

• Neurotrophic tyrosine kinase receptor (NTRK) gene family encodes tropomyosin receptor kinases (TRKs).
• NTRK gene rearrangements are rare oncogenic drivers in pediatric and adult cancers, more prevalent in pediatric populations.
• Altered NTRK genes lead to constitutive TRK activation, promoting carcinogenesis.

Purpose of the Study:

• To review studies on NTRK alterations in pediatric central nervous system tumors.
• To provide an overview of first and second-generation TRK inhibitors (TRKi) for clinical practice.
• To discuss the emergence of resistance to first-generation TRKi and the development of newer agents.

Main Methods:

• Literature review of studies on NTRK alterations in pediatric central nervous system tumors.
• Analysis of clinical data on the efficacy of TRK inhibitors (TRKi).
• Discussion of resistance mechanisms and development of next-generation TRKi.

Main Results:

• First-generation TRK inhibitor larotrectinib demonstrated histologic-agnostic activity against NTRK fusion tumors.
• Resistance to first-generation TRKi has been observed, necessitating the development of second-generation inhibitors.
• Second-generation TRKi, including selitrectinib and repotrectinib, are under development to overcome resistance.

Conclusions:

• NTRK alterations are significant oncogenic drivers in various cancers, particularly in pediatric populations.
• TRK inhibitors represent a targeted therapy approach with demonstrated efficacy against NTRK fusion tumors.
• Ongoing research into second-generation TRKi is crucial for overcoming treatment resistance and improving patient outcomes.