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Cancer Discov. 2016 Oct;6(10):1118-1133. Epub 2016 Jul 18.

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

Author information

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.

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.

SIGNIFICANCE:

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.

PMID:
27432227
PMCID:
PMC5050111
DOI:
10.1158/2159-8290.CD-16-0596
[Indexed for MEDLINE]
Free PMC Article

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