Sequential ALK Inhibitors Can Select for Lorlatinib-Resistant Compound <i>ALK</i> Mutations in ALK-Positive Lung Cancer
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- Satoshi Yoda
- 1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
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- Jessica J. Lin
- 1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
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- Michael S. Lawrence
- 1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
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- Benjamin J. Burke
- 4Pfizer Worldwide Research and Development, La Jolla, California.
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- Luc Friboulet
- 5Gustave Roussy Cancer Campus, Université Paris Saclay, INSERM U981, Paris, France.
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- Adam Langenbucher
- 1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
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- Leila Dardaei
- 1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
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- Kylie Prutisto-Chang
- 1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
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- Ibiayi Dagogo-Jack
- 1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
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- Sergei Timofeevski
- 4Pfizer Worldwide Research and Development, La Jolla, California.
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- Harper Hubbeling
- 1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
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- Justin F. Gainor
- 1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
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- Lorin A. Ferris
- 1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
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- Amanda K. Riley
- 1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
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- Krystina E. Kattermann
- 1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
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- Daria Timonina
- 1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
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- Rebecca S. Heist
- 1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
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- A. John Iafrate
- 6Cancer Center and Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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- Cyril H. Benes
- 1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
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- Jochen K. Lennerz
- 6Cancer Center and Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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- Mari Mino-Kenudson
- 6Cancer Center and Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
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- Jeffrey A. Engelman
- 7Novartis Institutes for BioMedical Research, Cambridge, Massachusetts.
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- Ted W. Johnson
- 4Pfizer Worldwide Research and Development, La Jolla, California.
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- Aaron N. Hata
- 1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
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- Alice T. Shaw
- 1Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts.
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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
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- Cancer Discovery
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Cancer Discovery 8 (6), 714-729, 2018-05-31
American Association for Cancer Research (AACR)