Background: The basis of sorafenib activity in desmoid tumors (DT) is poorly understood and predictive markers have not been defined. Activation of beta-catenin transcription target c-ABL by PDGFRbeta is associated with accumulation of EGR1 and increased sorafenib sensitivity in vitro, but in tumors, elevated EGR1 is associated with sorafenib resistance. Here we evaluate whether environmental signaling pathways outside of PDGFRbeta modify EGR1 levels in DT and regulate sorafenib response. Methods: A lentiviral shRNA screen targeting genes highly expressed in DT was performed in primary DT cell line (DES9525T). Potentially mitogenic genes encoding cell surface receptors were validated in DES8163T. Following treatment with drugs, shRNA directed at MET/ITGAV, HGF or vitronectin, cell proliferation, gene expression and protein analysis were assayed using CyQuant, RT-PCR and immunoblot, respectively. Synergy to drug treatments was assessed using Synergyfinder web (v3.0). Results: The custom screen identified both MET and ITGAV as affecting DT cell proliferation (35 and 31% decrease in knock-downs [KDs], respectively, p≤0.01). Supplementation of DT cell cultures with HGF or vitronectin conversely promoted desmoid proliferation (1.9 and 1.7-fold, respectively, p≤0.01) and increased the IC 50 of sorafenib in DT cells (from 5.2 and 5.7µM to 7.3 and 7.6µM). Growth of DT cells on vitronectin-coated plates was associated with increased phosphorylation of FAK but also PDGFRbeta, ERK1/2 and the canonical c-ABL target CrkL; vitronectin exposure led to EGR1 accumulation in cells. ITGAV KD or treatment of cells with the FAK inhibitor defactinib abrogated this response and increased cell sensitivity to sorafenib with combined sorafenib/defactinib treatment having a synergistic effect on DT proliferation (HAS synergy score 19). Stimulation of cells with HGF also resulted in phosphorylation of c-MET, AKT, ERK1/2, and CrkL, led to EGR1 accumulation and increased FAK phosphorylation consistent with reported HGF/c-MET role in integrin signaling regulation; this was inhibited by MET KD. Treatment of DT cells with MET inhibitor tivantinib was additive with sorafenib while HGF supplementation was associated with increased synergy score when assessing combined sorafenib and FAK inhibitor defactinib (HAS synergy score 12 vs. 15). Conclusions: Together, these findings demonstrate that HGF/MET and integrin-alphaV/FAK signaling each promote DT proliferation and sorafenib resistance. This is likely related to activation of downstream ERK/EGR1 in a manner not targetable by the PDGFRbeta inhibitor. C-MET and integrin signaling pathway components may represent appropriate molecules to assess as markers predictive of sorafenib response in DT patients.