The anaplastic lymphoma kinase (ALK) is chromosomally rearranged in a subset of 
certain cancers, including 2% to 7% of non-small cell lung cancers (NSCLC) and 
∼70% of anaplastic large cell lymphomas (ALCL). The ALK kinase inhibitors 
crizotinib and ceritinib are approved for relapsed ALK(+) NSCLC, but acquired 
resistance to these drugs limits median progression-free survival on average to 
∼10 months. Kinase domain mutations are detectable in 25% to 37% of resistant 
NSCLC samples, with activation of bypass signaling pathways detected frequently 
with or without concurrent ALK mutations. Here we report that, in contrast to 
NSCLC cells, drug-resistant ALCL cells show no evidence of bypassing ALK by 
activating alternate signaling pathways. Instead, drug resistance selected in 
this setting reflects upregulation of ALK itself. Notably, in the absence of 
crizotinib or ceritinib, we found that increased ALK signaling rapidly arrested 
or killed cells, allowing a prolonged control of drug-resistant tumors in vivo 
with the administration of discontinuous rather than continuous regimens of drug 
dosing. Furthermore, even when drug resistance mutations were detected in the 
kinase domain, overexpression of the mutant ALK was toxic to tumor cells. We 
confirmed these findings derived from human ALCL cells in murine pro-B cells 
that were transformed to cytokine independence by ectopic expression of an 
activated NPM-ALK fusion oncoprotein. In summary, our results show how ALK 
activation functions as a double-edged sword for tumor cell viability, with 
potential therapeutic implications.