AMP case report: MYC amplification identified in an EML4-ALK-positive lung adenocarcinoma with primary resistance to targeted therapy

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Resistance to ALK inhibitors due to MYC amplification has been reported. Rihawi, et al.,²⁰ reported the presence of ALK rearrangement together with MYC amplification in a patient with stage IV NSCLC who failed to respond to crizotinib and ceritinib and had rapid disease progression. Based on in vitro studies using a human EML4-ALK–rearranged NSCLC cell line with MYC overexpression, these cells showed reduced sensitivity to crizotinib and alectinib that was reversed by MYC inhibitors and CDK4/6 inhibitors.²⁰

Another study by Alidousty, et al.,²¹ investigated a possible mechanism for MYC-dependent resistance to ALK inhibitors in TP53-mutated ALK-positive NSCLC patients. They propose that MYC amplification leads to increased expression of the EML4-ALK fusion gene by binding its promoter, causing resistance to ALK inhibitors.

Our case further supports the notion that MYC amplification may be pathogenetically linked to primary resistance in ALK-rearranged NSCLC and is associated with a poorer outcome. MYC inhibition (either directly or through CDK4/6 inhibitors) may overcome this resistance mechanism.¹²

However, it is worth mentioning that MYC amplification-related potential primary resistance to EGFR TKIs was also reported in lung adenocarcinoma patients with EGFR-activating mutations.²²

Conclusion. We report a case of primary resistance to ALK inhibitors in EML4-ALK-positive lung adenocarcinoma with concomitant MYC amplification. The few similar cases reported in the literature have had a more aggressive clinical course compared with other ALK-rearranged NSCLC cases. We highlight this case because it demonstrates the important role of MYC amplification in the molecular mechanism of primary resistance to ALK inhibitors; assessment of MYC amplification for such patients may help guide prognostication and therapy. Patients with ALK-rearranged NSCLC and MYC amplification may need other agents against downstream targets, such as CDK4/6 inhibitors, to overcome MYC amplification-associated primary resistance to ALK inhibitors. However, given the limited number of cases reported, further study is needed to make definitive conclusions regarding precision therapy in this clinical setting.

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Dr. Yang was instructor (at the time the case report was written), Department of Laboratory Medicine and Pathology; Dr. Dolan is associate professor, Department of Laboratory Medicine and Pathology; Dr. Qin is a fellow, Division of Hematology, Oncology and Transplantation; Dr. Patel is associate professor of medicine, Division of Hematology, Oncology and Transplantation; Dr. Yohe is associate professor, Department of Laboratory Medicine and Pathology; and Dr. Nelson is associate professor, Department of Laboratory Medicine and Pathology—all at the University of Minnesota Medical School, Minneapolis. Dr. Yang is now assistant professor of clinical pathology and laboratory medicine, University of Pennsylvania Perelman School of Medicine.