SUMMARYInflammatory myofibroblastic tumor (IMT) is a distinctive mesenchymal neoplasm characterized by a spindle-cell proliferation with an inflammatory infiltrate. Approximately half of IMTs carry rearrangements of the anaplastic lymphoma kinase (ALK) locus on chromosome 2p23, causing aberrant ALK expression. We report a sustained partial response to the ALK inhibitor crizotinib (PF-02341066, Pfizer) in a patient with ALK-translocated IMT, as compared with no observed activity in another patient without the ALK translocation. These results support the dependence of ALK-rearranged tumors on ALK-mediated signaling and suggest a therapeutic strategy for genomically identified patients with the aggressive form of this soft-tissue tumor.Inflammatory myofibroblastic tumors (IMTS) occur primarily during the first two decades of life and typically arise in the lung, retroperitoneum, or abdominopelvic region. 1,2 Abdominal tumors may be multifocal. Lesional cells are predominantly myofibroblasts in a myxoid to collagenous stroma admixed with inflammatory cells. 2,3 Local recurrence may occur after initial surgery, with a low risk of distant metastases, 1,2 so that IMTs are considered to be soft-tissue tumors of intermediate biologic potential, with a small fraction behaving aggressively. 4 Rearrangements involving the ALK locus on chromosome 2p23 have been documented in approximately 50% of IMTs. 5,6 ALK aneuploidy has also been described, with a gain in copy number without rearrangement. 5 Among cancers with rearrangements, several fusion partners have been identified that serve to constitutively activate ALK. 7-10 ALK expression reliably correlates with ALK rearrangement. 11 Distant metastases occur primarily in ALKnegative IMTs, but local recurrence occurs regardless of ALK expression. 5 Several ALK fusion proteins, including TPM3-ALK found in IMT, induce transformation in cell lines and animal models, 13 a finding that suggests that ALK rearrangement may define a subgroup of IMTs that is sensitive to targeted kinase inhibition. We therefore enrolled two patients with IMT in a dose-escalation phase 1 trial of crizotinib, an orally bioavailable ATP-competitive inhibitor of the ALK and MET tyrosine kinases. 14,15 CASE REPORTSPatient 1 was a 44-year-old man who had been well until May 2007, when he reported having early satiety and abdominal pain. Computed tomography (CT) of the abdomen and pelvis revealed ascites, a mass in the right upper quadrant, and omental caking. The results of esophagogastroduodenoscopy and colonoscopy were unremarkable. The patient then underwent paracentesis. Combined 18 F-fluorodeoxyglucose positron-emission tomography and CT (FDG-PET-CT) revealed hypermetabolic masses in the abdomen and pelvis. In June 2007, he underwent exploratory laparotomy, which showed massive omental caking with discrete, round, gelatinous, grape-size tumor nodules and extensive peritoneal disease. Maximal tumor debulking was performed along with catheter placement to facilitate administration of a hyperthermic periton...

The ALK kinase inhibitor crizotinib (PF-02341066) is clinically effective in patients with ALK-translocated cancers, but its efficacy will ultimately be limited by acquired drug resistance. Here we report the identification of a secondary mutation in ALK, F1174L, as one cause of crizotinib resistance in a patient with an inflammatory myofibroblastic tumor (IMT) harboring a RANBP2-ALK translocation who progressed while on crizotinib therapy. When present in cis with an ALK translocation, this mutation (also detected in neuroblastomas) causes an increase in ALK phosphorylation, cell growth, and downstream signaling. Furthermore, the F1174L mutation inhibits crizotinib-mediated downregulation of ALK signaling and blocks apoptosis in RANBP2-ALK Ba/F3 cells. A chemically distinct ALK inhibitor, TAE684, and the HSP90 inhibitor 17-AAG are both effective in models harboring the F1174L ALK mutation. Our findings highlight the importance of studying drug resistance mechanisms in order to develop effective clinical treatments for patients with ALK-translocated cancers.