ALK rearranged non–small cell lung carcinoma with EML4-NTRK3 fusion as a possible mechanism of resistance to third-generation ALK inhibitors

Abstract

Objectives: Neurotrophic tropomyosin receptor kinase (NTRK) fusions might be an off-target resistance mechanism to ALK Tyrosine Kinase Inhibitors (TKIs) in the same way as it has been suggested with activating epidermal growth factor receptor (EGFR) TKIs. Materials and methods: DNA and RNA next-generation sequencing (NGS) was performed on the resected brain metastasis of a patient with advanced ALK Rearranged Non–Small Cell Lung Carcinoma (NSCLC) after resistance to several ALK TKIs including third generation ALK inhibitor, for pathological diagnosis and molecular resistance mechanism analysis. Results and conclusion: NGS revealed an EML4-NTRK3 fusion that was confirmed by Immunohistochemistry (IHC) and Fluorescence in situ hybridization (FISH). Despite having two potential targetable fusions, the patient did not respond to entrectinib, a multi-targeted pan-RTK, ROS1 and ALK inhibitor. NGS: analysis in blood or tissues samples should be encouraged once resistance develops to TKIs in patients with ALK rearrangements, as actionable fusions, mutations or amplifications might arise as resistance mechanism and some patients could benefit from targeted therapy.

Keywords

• Non-small cell lung cancer
• ALK fusion
• NTRK3 fusion
• ALK TKI resistance
• Next generation sequencing