Novel PLEC-EML4-ALK Double Fusion Underlying Crizotinib Resistance in a Metastatic Inflammatory Myofibroblastic...

ALK fusions are frequent oncogenic drivers in inflammatory myofibroblastic tumors. Treatment with crizotinib is effective in fusion-positive patients; however, acquired resistance remains a challenge. Here, we present a case of EML4-ALK-positive metastatic inflammatory myofibroblastic tumor that initially responded to crizotinib but developed resistance. The progressing lesion revealed the acquisition of a "double fusion" event in which EML4-ALK was additionally fused to PLEC to create a PLEC-EML4-ALK transcript. The double fusion was associated with an increase in ALK expression, mimicking the ALK fusion amplification that is a known mechanism of resistance to crizotinib in lung cancer. On transition to the more potent ALK inhibitor alectinib, the patient exhibited a dramatic response. Thus, the formation of a double fusion represents a novel and targetable mechanism of resistance to crizotinib.