title: Evidence Suggesting That Discontinuous Dosing of ALK Kinase Inhibitors May Prolong Control of ALK+ Tumors.
abstract: 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.
authors.affiliation: BIO5 Institute, University of Arizona, Tucson, Arizona.
authors.forename: Amit Dipak
authors.initials: AD
authors.lastname: Amin
authors.affiliation: Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, Arizona.
authors.forename: Soumya S
authors.initials: SS
authors.lastname: Rajan
authors.affiliation: Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, Arizona. Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: Winnie S
authors.initials: WS
authors.lastname: Liang
authors.affiliation: BIO5 Institute, University of Arizona, Tucson, Arizona.
authors.forename: Praechompoo
authors.initials: P
authors.lastname: Pongtornpipat
authors.affiliation: Undergraduate Biology Research Program, University of Arizona, Tucson, Arizona.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Groysman
authors.affiliation: Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, Arizona.
authors.forename: Edgar O
authors.initials: EO
authors.lastname: Tapia
authors.affiliation: Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, Arizona.
authors.forename: Tara L
authors.initials: TL
authors.lastname: Peters
authors.affiliation: Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, Arizona. Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: Lori
authors.initials: L
authors.lastname: Cuyugan
authors.affiliation: Integrated Cancer Genomics Division, Translational Genomics Research Institute, Phoenix, Arizona. Neurogenomics Division, Translational Genomics Research Institute, Phoenix, Arizona.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Adkins
authors.affiliation: Department of Pathology, University of Arizona, Tucson, Arizona.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Rimsza
authors.affiliation: BIO5 Institute, University of Arizona, Tucson, Arizona. Department of Medicine, University of Arizona, Tucson, Arizona. Statistics Graduate Interdisciplinary Program, University of Arizona, Tucson, Arizona.
authors.forename: Yves A
authors.initials: YA
authors.lastname: Lussier
authors.affiliation: Department of Medicine, University of Arizona, Tucson, Arizona.
authors.forename: Soham D
authors.initials: SD
authors.lastname: Puvvada
authors.affiliation: BIO5 Institute, University of Arizona, Tucson, Arizona. Department of Medicine, University of Arizona, Tucson, Arizona. Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona. schatzj@email.arizona.edu.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Schatz
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D000077547:Crizotinib; D004334:Drug Administration Schedule; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D017728:Lymphoma, Large-Cell, Anaplastic / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism; D011720:Pyrazoles / Q000008:administration & dosage*; D011725:Pyridines / Q000008:administration & dosage*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C107023:p80(NPM-ALK) protein; C000626173:ALK protein, human; C000626174:Alk protein, mouse; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases