The discovery of mutations in the ALK oncogene as the etiology of familial neuroblastoma and as somatically acquired in 14% of high-risk patients provided an opportunity to develop rational therapeutic strategies. Despite major advances in the clinical development of ALK inhibitors (Infarinato, 2015), it is unclear the exact mechanisms by which ALK inhibition abrogates tumorigenesis or, in some cases, activates compensatory pathways to promote drug resistance. The objective of our work was to identify immediate and adaptive changes in the kinome upon ALK inhibition. We used Multiplexed Inhibitor Beads coupled with Mass Spectrometry (MIB/MS) to quantitatively measure kinase activity dynamics on a proteomic scale. SY5Y cells that harbor one of the three hotspot mutations (F1174L) in the ALK gene were treated with either crizotinib or PF-06463922 at 10 nM, 100 nM, 1000 nM for 6 hours, 24 hours and 48 hours prior to MIB/MS analysis. Additionally, three patient-derived xenograft (PDX) models harboring F1174L (COG-N-453x) or the other two most-common mutations, R1275Q (NB-1643) and R1245C (Felix) were treated with either crizotinib (100 mg/kg a day) or PF-06463922 (10 mg/kg twice a day) for 2.5 days or 6.5 days prior to MIB/MS analysis. Although both crizotinib and PF-06463922 inhibited ALK, PF-06463922 preferentially inhibited a series of other kinases, correlating with the superior efficacy of PF-06463922 in pre-clinical studies. Across all three PDX models, Focal Adhesion Kinases (FAK1/2) were among the most statistically different from crizotinib and most strongly-inhibited by PF-06463922. Immunoblotting analysis of FAK phosphorylation (Y397) in cultured cells and tumors treated with both ALK inhibitors showed P-FAK downregulation, a finding that paralleled P-ALK (Y1278) levels in a dose-dependent manner and validated MIB/MS findings. FAK has a postulated role in controlling tumorigenesis in neuroblastoma, and we hypothesize that the preferential inhibition of FAK activity by PF-06463922 may play an important role. Whether FAK is regulated primarily downstream of ALK or jointly through alternative or compensatory signaling networks warrants further investigation.