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J Thorac Oncol. 2017 Jan;12(1):137-140. doi: 10.1016/j.jtho.2016.09.119. Epub 2016 Sep 22.

Emergence of Preexisting MET Y1230C Mutation as a Resistance Mechanism to Crizotinib in NSCLC with MET Exon 14 Skipping.

Author information

1
Chao Family Comprehensive Cancer Center, Department of Medicine, Division of Hematology-Oncology, University of California Irvine School of Medicine, Orange, California. Electronic address: Ignatius.ou@uci.edu.
2
Foundation Medicine, Inc., Cambridge, Massachusetts.
3
The Angeles Clinic and Research Institute, Los Angeles, California.
4
Chao Family Comprehensive Cancer Center, Department of Medicine, Division of Hematology-Oncology, University of California Irvine School of Medicine, Orange, California; Long Beach Veterans Administration Hospital, Long Beach, California.

Abstract

INTRODUCTION:

MET proto-oncogene, receptor tyrosine kinase gene exon 14 skipping (METex14) alterations represent a unique subset of oncogenic drivers in NSCLC. Preliminary clinical activity of crizotinib against METex14-positive NSCLC has been reported. The full spectrum of resistance mechanisms to crizotinib in METex14-positive NSCLC remains to be identified.

METHODS:

Hybrid capture-based comprehensive genomic profiling performed on a tumor specimen obtained at diagnosis, and a hybrid capture-based assay of circulating tumor DNA (ctDNA) at the time of progression during crizotinib treatment was assessed in a pairwise fashion.

RESULTS:

A METex14 alteration (D1010H) was detected in the pretreatment tumor biopsy specimen, as was MET proto-oncogene, receptor tyrosine kinase (MET) Y1230C, retrospectively, at very low frequency (0.3%). After a confirmed response during crizotinib treatment for 13 months followed by progression, both MET proto-oncogene, receptor tyrosine kinase gene Y1230C and D1010H were detected prospectively in the ctDNA.

CONCLUSION:

Emergence of the preexisting MET Y1230C likely confers resistance to crizotinib in this case of METex14-positive NSCLC. Existence of pretreatment MET Y1230C may eventually modulate the response of METex14-positive NSCLC to type I MET tyrosine kinase inhibitors. Noninvasive plasma-based ctDNA assays can provide a convenient method to detect resistance mutations in patients with previously known driver mutations.

KEYWORDS:

Circulating tumor DNA; Crizotinib; MET Y1230C; MET exon 14 skipping; Resistance mutation

PMID:
27666659
DOI:
10.1016/j.jtho.2016.09.119
[Indexed for MEDLINE]
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