Introduction: Activation of the tyrosine-kinase domain of anaplastic lymphoma kinase (ALK) drives malignant growth in subsets of several cancers as part of oncogenic fusions resulting from chromosomal rearrangements. ALK stimulates several oncogenic pathways, including JAK/STAT3, MEK/ERK, and PI3K/AKT. Clinically, 70% of anaplastic large-cell lymphoma (ALCL) and ~5% of nonsmall-cell lung cancer (NSCLC) are ALK+. ALK tyrosine-kinase inhibitors (TKIs) are approved for treatment of NSCLC and are under investigation in ALCL. Clinical resistance in lung cancer typically develops within 10 to 12 months is due to, most commonly, activation of alternate pathways or second-site kinase-domain mutations. We and others previously reported that, unlike NSCLC, ALCL tumor cells have great difficulty finding alternate pathways to replace ALK and instead upregulate expression of the NPM1-ALK fusion to maintain survival during inhibitor exposure. Strikingly, we found a toxic overdose of ALK signaling when inhibitors are withdrawn from overexpressing cells, triggering death. Here, we explore the mechanisms by which ALK overactivation drives cellular toxicity. Materials and Methods: We have generated multiple models of ALK+ ALCL with resistance to all generations ALK inhibitors. We employed RNAseq and phosphoproteomics to reveal candidate drivers of death upon ALK overexpression. We have generated multiple variant alleles of NPM1-ALK that enable us to interrogate the role of ALK's fusion partner in mediating these effects. Results: All generations of ALK inhibitors drive NPM1-ALK overexpression as the most frequent resistance mechanism in ALCL, but increased ALK activity upon inhibitor withdrawal is universally toxic. Extensive interrogations with targeted inhibitors and genetic approaches revealed that none of ALK's well-characterized downstream pathways is a key driver of overdose toxicity. Interestingly, while overexpression of NPM1-ALK confers selective disadvantage, elevated levels of activated ALK kinase domain alone do not. RNAseq analysis reveals hyperstimulation of protein biogenesis and RNA processing as cells die due to NPM1-ALK overdose. Phosphoproteomics results align with RNAseq data showing increased phosphorylation of proteins driving the same pathways. Taken together our results show the NPM1 translocation partner plays a key role driving NPM1-ALK overdose in ALCL by promoting phosphorylation of novel substrates. Conclusions: In contrast to ALK+ NSCLC, ALCL cannot easily bypass a need for ALK by activating alternate pathways. NPM1-ALK overexpression-driven toxicity is partner dependent, driving death associated with hyperactivation of protein and RNA processing pathways. Drugs that drive ALK toward phosphorylation of noncanonical substrates therefore represent a novel therapeutic strategy worth pursuing in ALCL and other ALK-driven malignancies. Keywords: ALK; anaplastic large cell lymphoma (ALCL)