TRKing down drug resistance in NTRK fusion-positive cancers^†

Area of Science:

• Oncology
• Molecular Pathology
• Genetics

Background:

• NTRK fusion-positive soft tissue sarcomas are rare but aggressive tumors.
• Targeted therapies like tyrosine kinase inhibitors (TKIs) show promise but resistance can develop.
• Understanding resistance mechanisms is crucial for improving treatment strategies.

Purpose of the Study:

• To establish patient-derived ex vivo models of NTRK fusion-positive soft tissue sarcoma.
• To characterize the molecular mechanisms of resistance to TKIs, specifically entrectinib.
• To identify potential combination therapies to overcome TKI resistance.

Main Methods:

• Development of patient-derived ex vivo models.
• Exposure of models to escalating concentrations of entrectinib to induce resistance.
• Genomic analysis to identify mutations in resistant clones.
• Analysis of signaling pathway activation (PI3K/AKT/mTOR and Ras/Raf/MEK/ERK).
• Inhibitor screening to identify potential combination agents.

Main Results:

• Resistant clones emerged after prolonged entrectinib exposure.
• A novel inactivating mutation in the NF2 gene was identified in resistant clones.
• Acquired NF2 mutations were associated with increased PI3K/AKT/mTOR and Ras/Raf/MEK/ERK signaling.
• MEK and mTOR inhibitors were identified as potential combination agents.

Conclusions:

• Patient-derived ex vivo models are valuable tools for studying TKI resistance in soft tissue sarcoma.
• NF2 gene inactivation is a novel mechanism of entrectinib resistance in this context.
• Combination therapy with MEK and mTOR inhibitors may overcome acquired resistance to entrectinib.