On-Chip Drug Testing Of An Aggressive Intra-Abdominal Variant Of Inflammatory Myofibroblastic Tumor By Kinase Activity Profiling.

e14702 Background: A patient presented with an expansivetumor of the liver, which infiltrated diaphragm, duodenum, gastric wall, pancreas and gall bladder. Pathological examination revealed a tumor dominated by infiltrating sheets of epithelioid-to-round cells with a prominent inflammatory infiltrate. Immunohistochemistry showed a positive reaction for vimentin but stained negative for S100, HMB45, Aktin, Desmin, CD117, DOG1, WT1, CDK4, mdm2 and ALK. Diagnosis of an ALK negative aggressive intra-abdominal variant of Inflammatory Myofibroblastic Tumor (IMT) was established. While it is know that approximately 50% of IMTs contain clonal rearrangements involving the ALK gene (Am. J. Surg. Pathol. 2011 135-144), little is known about the ALK-negative variant. The aim of the current study was to gain insights in potential aberrant signaling pathways in this rare tumor and potentially identify alternative druggable pathways. Methods: Kinase activity profiles of the tumor lysate were generated on PamChip peptide microarrays in the presence and absence of a concentration series of the protein kinase inhibitors (PKIs) erlotinib, imatinib, sorafenib, masitinib, crenolanib and tivozanib. Inhibitor effects on this IMT tumor lysate were compared to those on lysates from other tumor types, followed by bioinformatic analysis. Results: Comparing the different kinase inhibition profiles, erlotinib was the least effective inhibitor, while sorafenib and imatinib inhibited phosphorylation of a set of peptides that are known to be substrates for their kinase targets c-KIT, PDGFRα and PDGFRβ. The degree of inhibition in the IMT sample was higher than in tumor samples where these drugs are approved like CML and RCC (as well as in non-approved indications like CRC and AML). In the closely related sarcoma GIST, these kinases are successful targets. Additional prove of their involvement in this IMT variant was found in the positive inhibition profiles using crenolanib and masitinib. Conclusions: c-Kit and PDGFR and corresponding kinase inhibitors would be a pathway/drug combination of choice for drug development in this variant of IMT.