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

• Published in: Current problems in cancer. Case reports 2021-12, Vol.4, p.100124, Article 100124
• Main Authors: Corral de la Fuente, Elena, Benito Berlinches, Amparo, Gomez Rueda, Ana, Olmedo García, María Eugenia, Lage Alfranca, Yolanda, Lario, Margaret, Santón Roldán, Almudena, Garrido, Pilar
• Format: Article
• Language: English
• Subjects: ALK fusion; ALK TKI resistance; Next generation sequencing; Non-small cell lung cancer; NTRK3 fusion
• ISSN: 2666-6219; 2666-6219
• DOI: 10.1016/j.cpccr.2021.100124

•Echinoderm microtubule associated protein-like 4 (EML4)- anaplastic lymphoma kinase (ALK) fusion is the most common in NonSmall Cell Lung Cancer (NSCLC). Fluorescence in situ hybridization (FISH) has been regarded as the gold standard method for detecting ALK rearrangement. However, FISH is not able to identify some of the variants, new partner genes, ALK double fusions or co-alterations that might provide different response to ALK inhibitors.•Despite of the initial benefit, the use of ALK inhibitors leads to acquired drug resistance in most patients with advanced NSCLC. Neurotrophic tropomyosin receptor kinase (NTRK) fusions might be an off-target resistance mechanism to ALK Tyrosine Kinase Inhibitors (TKIs).•Serial Next-generation sequencing (NGS) analysis in blood or tissues samples should be encouraged once resistance develops to TKIs in patients ALK rearrangements, as some actionable fusions, mutations or amplifications have been shown to arise as resistance mechanism. 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. 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. 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. 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.