title: Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer.
abstract: Advanced, anaplastic lymphoma kinase (ALK)-positive lung cancer is currently treated with the first-generation ALK inhibitor crizotinib followed by more potent, second-generation ALK inhibitors (e.g., ceritinib and alectinib) upon progression. Second-generation inhibitors are generally effective even in the absence of crizotinib-resistant ALK mutations, likely reflecting incomplete inhibition of ALK by crizotinib in many cases. Herein, we analyzed 103 repeat biopsies from ALK-positive patients progressing on various ALK inhibitors. We find that each ALK inhibitor is associated with a distinct spectrum of ALK resistance mutations and that the frequency of one mutation, ALKG1202R, increases significantly after treatment with second-generation agents. To investigate strategies to overcome resistance to second-generation ALK inhibitors, we examine the activity of the third-generation ALK inhibitor lorlatinib in a series of ceritinib-resistant, patient-derived cell lines, and observe that the presence of ALK resistance mutations is highly predictive for sensitivity to lorlatinib, whereas those cell lines without ALK mutations are resistant.
  
  
  
  Secondary ALK mutations are a common resistance mechanism to second-generation ALK inhibitors and predict for sensitivity to the third-generation ALK inhibitor lorlatinib. These findings highlight the importance of repeat biopsies and genotyping following disease progression on targeted therapies, particularly second-generation ALK inhibitors. Cancer Discov; 6(10); 1118-33. ©2016 AACRSee related commentary by Qiao and Lovly, p. 1084This article is highlighted in the In This Issue feature, p. 1069.
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
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authors.lastname: Gainor
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
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authors.lastname: Dardaei
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Satoshi
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authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. Gustave Roussy Cancer Campus, Université Paris Saclay, INSERM U981, Paris, France.
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authors.lastname: Friboulet
authors.affiliation: Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors.forename: Ignaty
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authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
authors.forename: Ryohei
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authors.lastname: Katayama
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Ibiayi
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authors.affiliation: Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
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authors.lastname: Gadgeel
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
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authors.lastname: Schultz
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
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authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
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authors.lastname: Chin
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
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authors.lastname: Parks
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Dana
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authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Richard H
authors.initials: RH
authors.lastname: DiCecca
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Elizabeth
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authors.lastname: Lockerman
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
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authors.lastname: Huynh
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Jennifer
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authors.lastname: Logan
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Lauren L
authors.initials: LL
authors.lastname: Ritterhouse
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
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authors.initials: LP
authors.lastname: Le
authors.affiliation: Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Ashok
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authors.lastname: Muniappan
authors.affiliation: Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Subba
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authors.lastname: Digumarthy
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Colleen
authors.initials: C
authors.lastname: Channick
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Colleen
authors.initials: C
authors.lastname: Keyes
authors.affiliation: Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
authors.forename: Gad
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authors.lastname: Getz
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Dora
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authors.lastname: Dias-Santagata
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Heist
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Jochen
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authors.lastname: Lennerz
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Lecia V
authors.initials: LV
authors.lastname: Sequist
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Cyril H
authors.initials: CH
authors.lastname: Benes
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: A John
authors.initials: AJ
authors.lastname: Iafrate
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Mari
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authors.lastname: Mino-Kenudson
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. ashaw1@partners.org jeffrey.engelman@novartis.com.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Engelman
authors.affiliation: Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. ashaw1@partners.org jeffrey.engelman@novartis.com.
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mesh_terms: D000631:Aminopyridines; D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D006801:Humans; D007769:Lactams; D047029:Lactams, Macrocyclic / Q000494:pharmacology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles; D011743:Pyrimidines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics*; D013450:Sulfones / Q000494:pharmacology
chemical_list: D000631:Aminopyridines; D007769:Lactams; D047029:Lactams, Macrocyclic; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D013450:Sulfones; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; C586847:ceritinib; C000590786:lorlatinib