title: Mechanisms of acquired crizotinib resistance in ALK-rearranged lung Cancers.
abstract: Most anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancers (NSCLCs) are highly responsive to treatment with ALK tyrosine kinase inhibitors (TKIs). However, patients with these cancers invariably relapse, typically within 1 year, because of the development of drug resistance. Herein, we report findings from a series of lung cancer patients (n = 18) with acquired resistance to the ALK TKI crizotinib. In about one-fourth of patients, we identified a diverse array of secondary mutations distributed throughout the ALK TK domain, including new resistance mutations located in the solvent-exposed region of the adenosine triphosphate-binding pocket, as well as amplification of the ALK fusion gene. Next-generation ALK inhibitors, developed to overcome crizotinib resistance, had differing potencies against specific resistance mutations. In addition to secondary ALK mutations and ALK gene amplification, we also identified aberrant activation of other kinases including marked amplification of KIT and increased autophosphorylation of epidermal growth factor receptor in drug-resistant tumors from patients. In a subset of patients, we found evidence of multiple resistance mechanisms developing simultaneously. These results highlight the unique features of TKI resistance in ALK-positive NSCLCs and provide the rationale for pursuing combinatorial therapeutics that are tailored to the precise resistance mechanisms identified in patients who relapse on crizotinib treatment.
authors.affiliation: Massachusetts General Hospital Cancer Center, Boston, MA 02129, USA.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Katayama
authors.forename: Alice T
authors.initials: AT
authors.lastname: Shaw
authors.forename: Tahsin M
authors.initials: TM
authors.lastname: Khan
authors.forename: Mari
authors.initials: M
authors.lastname: Mino-Kenudson
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Solomon
authors.forename: Balazs
authors.initials: B
authors.lastname: Halmos
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Jessop
authors.forename: John C
authors.initials: JC
authors.lastname: Wain
authors.forename: Alan Tien
authors.initials: AT
authors.lastname: Yeo
authors.forename: Cyril
authors.initials: C
authors.lastname: Benes
authors.forename: Lisa
authors.initials: L
authors.lastname: Drew
authors.forename: Jamal Carlos
authors.initials: JC
authors.lastname: Saeh
authors.forename: Katherine
authors.initials: K
authors.lastname: Crosby
authors.forename: Lecia V
authors.initials: LV
authors.lastname: Sequist
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
mesh_terms: D000077548:Anaplastic Lymphoma Kinase; D045744:Cell Line, Tumor; D000077547:Crizotinib; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics*; D009154:Mutation; D016133:Polymerase Chain Reaction; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011720:Pyrazoles / Q000627:therapeutic use*; D011725:Pyridines / Q000627:therapeutic use*; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases