title: TKI sensitivity patterns of novel kinase-domain mutations suggest therapeutic opportunities for patients with resistant ALK+ tumors.
abstract: The anaplastic lymphoma kinase (ALK) protein drives tumorigenesis in subsets of several tumors through chromosomal rearrangements that express and activate its C-terminal kinase domain. In addition, germline predisposition alleles and acquired mutations are found in the full-length protein in the pediatric tumor neuroblastoma. ALK-specific tyrosine kinase inhibitors (TKIs) have become important new drugs for ALK-driven lung cancer, but acquired resistance via multiple mechanisms including kinase-domain mutations eventually develops, limiting median progression-free survival to less than a year. Here we assess the impact of several kinase-domain mutations that arose during TKI resistance selections of ALK+ anaplastic large-cell lymphoma (ALCL) cell lines. These include novel variants with respect to ALK-fusion cancers, R1192P and T1151M, and with respect to ALCL, F1174L and I1171S. We assess the effects of these mutations on the activity of six clinical inhibitors in independent systems engineered to depend on either the ALCL fusion kinase NPM-ALK or the lung-cancer fusion kinase EML4-ALK. Our results inform treatment strategies with a likelihood of bypassing mutations when detected in resistant patient samples and highlight differences between the effects of particular mutations on the two ALK fusions.
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Amit Dipak
authors.initials: AD
authors.lastname: Amin
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Lingxiao
authors.initials: L
authors.lastname: Li
authors.affiliation: Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Soumya S
authors.initials: SS
authors.lastname: Rajan
authors.affiliation: BIO5 Institute, University of Arizona, Tucson, AZ, USA.|Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, USA.
authors.forename: Vijay
authors.initials: V
authors.lastname: Gokhale
authors.affiliation: Undergraduate Biology Research Program, University of Arizona, Tucson, AZ, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Groysman
authors.affiliation: BIO5 Institute, University of Arizona, Tucson, AZ, USA.
authors.forename: Praechompoo
authors.initials: P
authors.lastname: Pongtornpipat
authors.affiliation: Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ, USA.
authors.forename: Edgar O
authors.initials: EO
authors.lastname: Tapia
authors.affiliation: Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ, USA.
authors.forename: Mengdie
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Medicine, Division of Hematology-Oncology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Schatz
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; C522504:EML4-ALK fusion protein, human; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; C107023:p80(NPM-ALK) protein; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases
keywords: alectinib; anaplastic lymphoma kinase; ceritinib; crizotinib; drug resistance