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J Thorac Oncol. 2014 Feb;9(2):248-53. doi: 10.1097/JTO.0000000000000050.

Identification and characterization of ALK kinase splicing isoforms in non-small-cell lung cancer.

Author information

1
*Department of Medicine, Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts; †Department of Pathology, Queen Mary Hospital, The University of Hong Kong, Hong Kong, China; and ‡Department of Medical Oncology, Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.

Abstract

INTRODUCTION:

Anaplastic lymphoma kinase (ALK) rearrangements are present in an important subset of non-small-cell lung cancer (NSCLC) and predict for response to the tyrosine kinase inhibitor crizotinib. In this study, we evaluated the yet unknown frequency and functional role of ALK splicing isoforms in NSCLC.

METHODS:

We analyzed 270 cases of NSCLC for ALK kinase domain splicing aberrations and in addition generated constructs with full-length echinoderm microtubule-associated protein-like 4 (EML4)-ALK (E13;A20) and a splicing isoform.

RESULTS:

Splicing isoforms of the kinase domain of ALK-including complete skipping of exon 23 (ALKdel23, ALK p.I1171fs*42) and exon 27 (ALKdel27, ALK p.T1312fs*0)-were identified in 11.1% (30 of 270 cases) of NSCLC, and these changes coexisted with ALK rearrangements, KRAS mutations, and EGFR mutations. ALK splicing isoforms were observed with full-length EML4-ALK in crizotinib-naive and treated NSCLCs. ALK T1312fs*0 was unable to render cells solely dependent on ALK signaling. Unlike EML4-ALK and EML4-ALK p.L1196M, EML4-ALK T1312fs*0 did not autophosphorylate ALK or other phosphotyrosine sites. Coexpression of equal amounts of EML4-ALK T1312fs*0 and EML4-ALK did not result in resistance to crizotinib, whereas coexpression of EML4-ALK L1196M with EML4-ALK resulted in resistance to inhibition of ALK by crizotinib.

CONCLUSIONS:

ALK kinase splicing isoforms were present in NSCLC and even if translated seemed to be nonfunctional variants of ALK.

PMID:
24419423
PMCID:
PMC4096850
DOI:
10.1097/JTO.0000000000000050
[Indexed for MEDLINE]
Free PMC Article

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