Targeting Wild-type NTRK in NTRK Fusion-Negative Lung Cancer Decreases Brain Metastases

Area of Science:

• Neuro-oncology
• Cancer Biology
• Pharmacology

Background:

• Central nervous system (CNS) metastases are common in lung cancer, with limited treatment options.
• Tyrosine kinase inhibitors (TKIs) show promise for brain metastases (BM) but are often limited to specific oncogenic drivers.
• Neurotrophic tyrosine receptor kinase (NTRK) inhibitors are effective for NTRK fusion-driven cancers, but wild-type NTRK activation in BM is less understood.

Purpose of the Study:

• To investigate the role of wild-type NTRK2 (WT-TrkB) in lung cancer brain metastases (BM).
• To determine if NTRK inhibitors can prevent or treat BM driven by WT-NTRK activation.

Main Methods:

• Assessed NTRK expression in primary lung tumors and BM.
• Investigated WT-TrkB signaling and proliferation in response to brain-derived neurotrophic factor (BDNF) and astrocyte-conditioned media.
• Evaluated the efficacy of entrectinib in vitro and in vivo models of lung cancer BM.

Main Results:

• WT-TrkB is expressed in lung cancer cells and activated by BDNF and astrocyte-derived factors, promoting proliferation.
• Entrectinib inhibited WT-TrkB signaling, reduced proliferation in vitro, and prevented BM colonization and progression in vivo.
• Entrectinib showed no significant effects on extracranial disease.

Conclusions:

• Brain-dependent activation of WT-NTRK signaling is critical for lung cancer BM.
• FDA-approved NTRK inhibitors can target non-fusion WT-NTRK function to prevent or decrease CNS metastases.
• This provides a rationale for expanding NTRK inhibitor use for BM prevention in relevant lung cancer subtypes.