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David S. Ettinger, MD, FACP, FCCP


Case Study in Advanced Lung Cancer: EML4-NTRK Gene Fusion and ALK Inhibitor Resistance

By: Julia Fiederlein
Posted: Monday, January 17, 2022

Studies have suggested that NTRK1 gene fusion may be a possible off-target resistance mechanism to EGFR tyrosine kinase inhibitors. However, according to Elena Corral de la Fuente, MD, of the Centro Integral Oncológico Clara Campal, Madrid, and colleagues, there are limited data regarding whether oncogenic kinase gene fusions may be off-target resistance mechanisms to ALK inhibitor therapy. A patient profile highlighting EML4-NTRK3 gene fusion as a possible mechanism of resistance to third-generation ALK inhibitor therapy in advanced EML4-ALK fusion–positive non–small cell lung cancer (NSCLC) was published in the journal Current Problems in Cancer: Case Reports.

After experiencing resistance to the first-, second-, and third-generation ALK inhibitors crizotinib, alectinib, and lorlatinib, respectively, DNA- and RNA-based next-generation sequencing was performed on the resected brain metastasis of a 56-year-old man with advanced ALK-rearranged NSCLC. An EML4-NTRK3 gene fusion was detected, and it was confirmed by immunohistochemistry and fluorescence in situ hybridization. Although the patient harbored two targetable gene fusions, he did not respond to treatment with the multitargeted pan-RTK, ROS1, and ALK inhibitor entrectinib.

“Though in the present case, the patient did not undergo genetic testing before ALK inhibitor treatment, we considered EML4-NTRK3 [gene] fusion as a possible off-target resistance mechanism to ALK tyrosine kinase inhibitors,” the investigators remarked. “Serial next-generation sequencing analysis in blood or tissue samples should be encouraged once resistance develops to tyrosine kinase inhibitors in patients with EGFR mutations and ALK or ROS1 rearrangements, as some actionable [gene] fusions, mutations, or amplifications have been shown to arise as resistance mechanisms.”

According to the investigators, further research is warranted to determine the activity of entrectinib in patients who were pretreated with ALK tyrosine kinase inhibitor therapy. The possible role of NTRK gene fusion as a mechanism of resistance to ALK tyrosine kinase inhibitor therapy should also be examined.

Disclosure: For full disclosures of the study authors, visit

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