Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant Compound <i>ALK</i> Mutations in ALK-Positive Lung Cancer

  • Satoshi Yoda
    1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
  • Jessica J. Lin
    1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
  • Michael S. Lawrence
    1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
  • Benjamin J. Burke
    4Pfizer Worldwide Research and Development, La Jolla, California.
  • Luc Friboulet
    5Gustave Roussy Cancer Campus, Université Paris Saclay, INSERM U981, Paris, France.
  • Adam Langenbucher
    1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
  • Leila Dardaei
    1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
  • Kylie Prutisto-Chang
    1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
  • Ibiayi Dagogo-Jack
    1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
  • Sergei Timofeevski
    4Pfizer Worldwide Research and Development, La Jolla, California.
  • Harper Hubbeling
    1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
  • Justin F. Gainor
    1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
  • Lorin A. Ferris
    1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
  • Amanda K. Riley
    1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
  • Krystina E. Kattermann
    1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
  • Daria Timonina
    1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
  • Rebecca S. Heist
    1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
  • A. John Iafrate
    6Cancer Center and Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
  • Cyril H. Benes
    1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
  • Jochen K. Lennerz
    6Cancer Center and Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
  • Mari Mino-Kenudson
    6Cancer Center and Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
  • Jeffrey A. Engelman
    7Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
  • Ted W. Johnson
    4Pfizer Worldwide Research and Development, La Jolla, California.
  • Aaron N. Hata
    1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
  • Alice T. Shaw
    1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.

この論文をさがす

説明

<jats:title>Abstract</jats:title> <jats:p>The cornerstone of treatment for advanced ALK-positive lung cancer is sequential therapy with increasingly potent and selective ALK inhibitors. The third-generation ALK inhibitor lorlatinib has demonstrated clinical activity in patients who failed previous ALK inhibitors. To define the spectrum of ALK mutations that confer lorlatinib resistance, we performed accelerated mutagenesis screening of Ba/F3 cells expressing EML4–ALK. Under comparable conditions, N-ethyl-N-nitrosourea (ENU) mutagenesis generated numerous crizotinib-resistant but no lorlatinib-resistant clones harboring single ALK mutations. In similar screens with EML4–ALK containing single ALK resistance mutations, numerous lorlatinib-resistant clones emerged harboring compound ALK mutations. To determine the clinical relevance of these mutations, we analyzed repeat biopsies from lorlatinib-resistant patients. Seven of 20 samples (35%) harbored compound ALK mutations, including two identified in the ENU screen. Whole-exome sequencing in three cases confirmed the stepwise accumulation of ALK mutations during sequential treatment. These results suggest that sequential ALK inhibitors can foster the emergence of compound ALK mutations, identification of which is critical to informing drug design and developing effective therapeutic strategies.</jats:p> <jats:p>Significance: Treatment with sequential first-, second-, and third-generation ALK inhibitors can select for compound ALK mutations that confer high-level resistance to ALK-targeted therapies. A more efficacious long-term strategy may be up-front treatment with a third-generation ALK inhibitor to prevent the emergence of on-target resistance. Cancer Discov; 8(6); 714–29. ©2018 AACR.</jats:p> <jats:p>This article is highlighted in the In This Issue feature, p. 663</jats:p>

収録刊行物

  • Cancer Discovery

    Cancer Discovery 8 (6), 714-729, 2018-05-31

    American Association for Cancer Research (AACR)

被引用文献 (16)*注記

もっと見る

詳細情報 詳細情報について

問題の指摘

ページトップへ