Evidence Suggesting That Discontinuous Dosing of ALK Kinase Inhibitors May Prolong Control of ALK+ Tumors

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