Oncogenic and drug-sensitive NTRK1 rearrangements in lung cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• The NTRK1 gene encodes the TRKA protein, a high-affinity nerve growth factor receptor.
• Gene fusions involving NTRK1 can lead to oncogenic activation.
• Identifying novel gene fusions is crucial for understanding cancer development and targeted therapy.

Purpose of the Study:

• To identify and characterize novel gene fusions involving the NTRK1 gene in lung cancer.
• To investigate the functional and oncogenic consequences of these NTRK1 gene fusions.
• To evaluate the therapeutic potential of TRKA kinase inhibitors in lung cancer with NTRK1 fusions.

Main Methods:

• Next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) were used to analyze tumor samples.
• Functional assays were performed to assess the kinase activity and oncogenic potential of identified fusions.
• Cell proliferation assays were conducted to evaluate the efficacy of TRKA kinase inhibitors.

Main Results:

• Two novel NTRK1 gene fusions, MPRIP-NTRK1 and CD74-NTRK1, were identified in lung cancer patients.
• These fusions result in constitutive activation of the TRKA kinase domain, promoting oncogenesis.
• Inhibition of TRKA kinase activity effectively suppressed cell growth in cells harboring these fusions.
• NTRK1 gene fusions were detected in 3.3% of lung cancer patients lacking other known oncogenic alterations.

Conclusions:

• MPRIP-NTRK1 and CD74-NTRK1 are novel oncogenic drivers in lung cancer.
• Targeting TRKA kinase activity with inhibitors represents a promising therapeutic strategy for lung cancer patients with NTRK1 fusions.