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      Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in ALK-Rearranged Lung Cancer.

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          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, ALK(G1202R), 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.

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          Author and article information

          Journal
          Cancer Discov
          Cancer discovery
          American Association for Cancer Research (AACR)
          2159-8290
          2159-8274
          Oct 2016
          : 6
          : 10
          Affiliations
          [1 ] Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts.
          [2 ] Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. Gustave Roussy Cancer Campus, Université Paris Saclay, INSERM U981, Paris, France.
          [3 ] Broad Institute of the Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts.
          [4 ] Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan.
          [5 ] Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
          [6 ] Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
          [7 ] Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts.
          [8 ] Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.
          [9 ] Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts. ashaw1@partners.org jeffrey.engelman@novartis.com.
          Article
          2159-8290.CD-16-0596 NIHMS804899
          10.1158/2159-8290.CD-16-0596
          5050111
          27432227

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