Functional analyses of mutations in receptor tyrosine kinase genes in Non-Small cell lung cancer: Double-Edged Sword of DDR2

Masato Terashima, Yosuke Togashi, Katsuaki Sato, Hiroshi Mizuuchi, Kazuko Sakai, Kenichi Suda, Yu Nakamura, Eri Banno, Hidetoshi Hayashi, Marco A. De Velasco, Yoshihiko Fujita, Shuta Tomida, Tetsuya Mitsudomi, Kazuto Nishio

Research output: Contribution to journalArticle

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Abstract

Purpose: This study investigated whether mutations of receptor tyrosine kinase (RTK) genes detected using next-generation sequencing (NGS) are suitable therapeutic targets. Experimental design: Fifty surgically resected non-small cell lung cancer (NSCLC) samples were target resequenced using NGS. We then investigated the functions of the identified RTK gene mutations, including their oncogenic potential, in vitro. Results: Mutations in RTK genes were found in 20 samples (EGFR, 15; ERBB4, 1; ALK, 1; DDR2, 2; FGFR1, 1), mutations in MAPK pathway genes were found in nine samples (KRAS, 7; NRAS, 1; BRAF, 2), and mutations in PI3K pathway genes were found in three samples (PIK3CA, 1; PTEN, 3). Among the mutations in RTKs, the functions of four mutations were unclear (ERBB4 D245G; DDR2 H246R and E655K; FGFR1 A263V). These mutations did not exhibit any transformational activities. Neither the phosphorylation nor the protein expressions of RTKs were changed by the DDR2 H246R, ERBB4 D245G, and FGFR1 A263V mutations, although the expression level of the DDR2 protein harboring the E655K mutation was particularly low. Collagen stimulation decreased cellular proliferation through p38 activation in the DDR2 wild-type-overexpressed cell lines, whereas the growthsuppressive effect was weakened in DDR2 E655K-overexpressed cell lines. Furthermore, the DDR2 E655K protein strongly bound to ubiquitin ligase E3 (Cbl-b), and the mutant protein expression was increased after treatment with a proteasome inhibitor. Conclusions: Our experimental findings suggest that RTK mutations are not always suitable as therapeutic targets. The DDR2 E655K mutation can play a role in cancer progression by reducing the growth-inhibitory effect of collagen.

Original languageEnglish
Pages (from-to)3663-3671
Number of pages9
JournalClinical Cancer Research
Volume22
Issue number14
DOIs
Publication statusPublished - Jul 15 2016
Externally publishedYes

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Receptor Protein-Tyrosine Kinases
Non-Small Cell Lung Carcinoma
Mutation
Genes
Collagen
Cell Line
Proteasome Inhibitors
Ubiquitin-Protein Ligases
Mutant Proteins
Phosphatidylinositol 3-Kinases
Research Design
Phosphorylation
Cell Proliferation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Functional analyses of mutations in receptor tyrosine kinase genes in Non-Small cell lung cancer : Double-Edged Sword of DDR2. / Terashima, Masato; Togashi, Yosuke; Sato, Katsuaki; Mizuuchi, Hiroshi; Sakai, Kazuko; Suda, Kenichi; Nakamura, Yu; Banno, Eri; Hayashi, Hidetoshi; De Velasco, Marco A.; Fujita, Yoshihiko; Tomida, Shuta; Mitsudomi, Tetsuya; Nishio, Kazuto.

In: Clinical Cancer Research, Vol. 22, No. 14, 15.07.2016, p. 3663-3671.

Research output: Contribution to journalArticle

Terashima, M, Togashi, Y, Sato, K, Mizuuchi, H, Sakai, K, Suda, K, Nakamura, Y, Banno, E, Hayashi, H, De Velasco, MA, Fujita, Y, Tomida, S, Mitsudomi, T & Nishio, K 2016, 'Functional analyses of mutations in receptor tyrosine kinase genes in Non-Small cell lung cancer: Double-Edged Sword of DDR2', Clinical Cancer Research, vol. 22, no. 14, pp. 3663-3671. https://doi.org/10.1158/1078-0432.CCR-15-2093
Terashima, Masato ; Togashi, Yosuke ; Sato, Katsuaki ; Mizuuchi, Hiroshi ; Sakai, Kazuko ; Suda, Kenichi ; Nakamura, Yu ; Banno, Eri ; Hayashi, Hidetoshi ; De Velasco, Marco A. ; Fujita, Yoshihiko ; Tomida, Shuta ; Mitsudomi, Tetsuya ; Nishio, Kazuto. / Functional analyses of mutations in receptor tyrosine kinase genes in Non-Small cell lung cancer : Double-Edged Sword of DDR2. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 14. pp. 3663-3671.
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abstract = "Purpose: This study investigated whether mutations of receptor tyrosine kinase (RTK) genes detected using next-generation sequencing (NGS) are suitable therapeutic targets. Experimental design: Fifty surgically resected non-small cell lung cancer (NSCLC) samples were target resequenced using NGS. We then investigated the functions of the identified RTK gene mutations, including their oncogenic potential, in vitro. Results: Mutations in RTK genes were found in 20 samples (EGFR, 15; ERBB4, 1; ALK, 1; DDR2, 2; FGFR1, 1), mutations in MAPK pathway genes were found in nine samples (KRAS, 7; NRAS, 1; BRAF, 2), and mutations in PI3K pathway genes were found in three samples (PIK3CA, 1; PTEN, 3). Among the mutations in RTKs, the functions of four mutations were unclear (ERBB4 D245G; DDR2 H246R and E655K; FGFR1 A263V). These mutations did not exhibit any transformational activities. Neither the phosphorylation nor the protein expressions of RTKs were changed by the DDR2 H246R, ERBB4 D245G, and FGFR1 A263V mutations, although the expression level of the DDR2 protein harboring the E655K mutation was particularly low. Collagen stimulation decreased cellular proliferation through p38 activation in the DDR2 wild-type-overexpressed cell lines, whereas the growthsuppressive effect was weakened in DDR2 E655K-overexpressed cell lines. Furthermore, the DDR2 E655K protein strongly bound to ubiquitin ligase E3 (Cbl-b), and the mutant protein expression was increased after treatment with a proteasome inhibitor. Conclusions: Our experimental findings suggest that RTK mutations are not always suitable as therapeutic targets. The DDR2 E655K mutation can play a role in cancer progression by reducing the growth-inhibitory effect of collagen.",
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AU - Terashima, Masato

AU - Togashi, Yosuke

AU - Sato, Katsuaki

AU - Mizuuchi, Hiroshi

AU - Sakai, Kazuko

AU - Suda, Kenichi

AU - Nakamura, Yu

AU - Banno, Eri

AU - Hayashi, Hidetoshi

AU - De Velasco, Marco A.

AU - Fujita, Yoshihiko

AU - Tomida, Shuta

AU - Mitsudomi, Tetsuya

AU - Nishio, Kazuto

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