Identification and Characterization of ALK Kinase Splicing Isoforms in Non-Small-Cell Lung Cancer

Lorena Lobo De Figueiredo-Pontes, Daisy Wing Sze Wong, Vicky Pui Chi Tin, Lap Ping Chung, Hiroyuki Yasuda, Norihiro Yamaguchi, Sohei Nakayama, Pasi Antero Jänne, Maria Pik Wong, Susumu Soeda Kobayashi, Daniel Botelho Costa

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)248-253
Number of pages6
JournalJournal of Thoracic Oncology
Volume9
Issue number2
DOIs
Publication statusPublished - 2014 Feb 1
Externally publishedYes

Keywords

  • Alternative splicing
  • Anaplastic lymphoma kinase
  • Crizotinib
  • Exon 23
  • Exon 27
  • Exon skipping
  • Kinase inhibitor
  • Lung cancer
  • Non-small-cell lung cancer
  • Tyrosine kinase

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

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  • Cite this

    De Figueiredo-Pontes, L. L., Wong, D. W. S., Tin, V. P. C., Chung, L. P., Yasuda, H., Yamaguchi, N., Nakayama, S., Jänne, P. A., Wong, M. P., Kobayashi, S. S., & Costa, D. B. (2014). Identification and Characterization of ALK Kinase Splicing Isoforms in Non-Small-Cell Lung Cancer. Journal of Thoracic Oncology, 9(2), 248-253. https://doi.org/10.1097/JTO.0000000000000050