Frequent amplification of receptor tyrosine kinase genes in welldifferentiated/ dedifferentiated liposarcoma

Naofumi Asano, Akihiko Yoshida, Sachiyo Mitani, Eisuke Kobayashi, Bunsyo Shiotani, Motokiyo Komiyama, Hiroyuki Fujimoto, Hirokazu Chuman, Hideo Morioka, Morio Matsumoto, Masaya Nakamura, Takashi Kubo, Mamoru Kato, Takashi Kohno, Akira Kawai, Tadashi Kondo, Hitoshi Ichikawa

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are closely related tumors commonly characterized by MDM2/CDK4 gene amplification, and lack clinically effective treatment options when inoperable. To identify novel therapeutic targets, we performed targeted genomic sequencing analysis of 19 WDLPS and 37 DDLPS tumor samples using a panel of 104 cancerrelated genes (NCC oncopanel v3) developed specifically for genomic testing to select suitable molecular targeted therapies. The results of this analysis indicated that these sarcomas had very few gene mutations and a high frequency of amplifications of not only MDM2 and CDK4 but also other genes. Potential driver mutations were found in only six (11%) samples; however, gene amplification events (other than MDM2 and CDK4 amplification) were identified in 30 (54%) samples. Receptor tyrosine kinase (RTK) genes in particular were amplified in 18 (32%) samples. In addition, growth of a WDLPS cell line with IGF1R amplification was suppressed by simultaneous inhibition of CDK4 and IGF1R, using palbociclib and NVP-AEW541, respectively. Combination therapy with CDK4 and RTK inhibitors may be an effective therapeutic option for WDLPS/DDLPS patients with RTK gene amplification.

Original languageEnglish
Pages (from-to)12941-12952
Number of pages12
JournalOncotarget
Volume8
Issue number8
DOIs
Publication statusPublished - 2017

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Liposarcoma
Receptor Protein-Tyrosine Kinases
Gene Amplification
Genes
Molecular Targeted Therapy
Mutation
Therapeutics
Sarcoma
Neoplasms
Cell Line
Growth

Keywords

  • Dedifferentiated liposarcoma
  • Liposarcoma
  • Next-generation sequencing
  • Receptor tyrosine kinase
  • Well-differentiated liposarcoma

ASJC Scopus subject areas

  • Oncology

Cite this

Asano, N., Yoshida, A., Mitani, S., Kobayashi, E., Shiotani, B., Komiyama, M., ... Ichikawa, H. (2017). Frequent amplification of receptor tyrosine kinase genes in welldifferentiated/ dedifferentiated liposarcoma. Oncotarget, 8(8), 12941-12952. https://doi.org/10.18632/oncotarget.14652

Frequent amplification of receptor tyrosine kinase genes in welldifferentiated/ dedifferentiated liposarcoma. / Asano, Naofumi; Yoshida, Akihiko; Mitani, Sachiyo; Kobayashi, Eisuke; Shiotani, Bunsyo; Komiyama, Motokiyo; Fujimoto, Hiroyuki; Chuman, Hirokazu; Morioka, Hideo; Matsumoto, Morio; Nakamura, Masaya; Kubo, Takashi; Kato, Mamoru; Kohno, Takashi; Kawai, Akira; Kondo, Tadashi; Ichikawa, Hitoshi.

In: Oncotarget, Vol. 8, No. 8, 2017, p. 12941-12952.

Research output: Contribution to journalArticle

Asano, N, Yoshida, A, Mitani, S, Kobayashi, E, Shiotani, B, Komiyama, M, Fujimoto, H, Chuman, H, Morioka, H, Matsumoto, M, Nakamura, M, Kubo, T, Kato, M, Kohno, T, Kawai, A, Kondo, T & Ichikawa, H 2017, 'Frequent amplification of receptor tyrosine kinase genes in welldifferentiated/ dedifferentiated liposarcoma', Oncotarget, vol. 8, no. 8, pp. 12941-12952. https://doi.org/10.18632/oncotarget.14652
Asano, Naofumi ; Yoshida, Akihiko ; Mitani, Sachiyo ; Kobayashi, Eisuke ; Shiotani, Bunsyo ; Komiyama, Motokiyo ; Fujimoto, Hiroyuki ; Chuman, Hirokazu ; Morioka, Hideo ; Matsumoto, Morio ; Nakamura, Masaya ; Kubo, Takashi ; Kato, Mamoru ; Kohno, Takashi ; Kawai, Akira ; Kondo, Tadashi ; Ichikawa, Hitoshi. / Frequent amplification of receptor tyrosine kinase genes in welldifferentiated/ dedifferentiated liposarcoma. In: Oncotarget. 2017 ; Vol. 8, No. 8. pp. 12941-12952.
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abstract = "Well-differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are closely related tumors commonly characterized by MDM2/CDK4 gene amplification, and lack clinically effective treatment options when inoperable. To identify novel therapeutic targets, we performed targeted genomic sequencing analysis of 19 WDLPS and 37 DDLPS tumor samples using a panel of 104 cancerrelated genes (NCC oncopanel v3) developed specifically for genomic testing to select suitable molecular targeted therapies. The results of this analysis indicated that these sarcomas had very few gene mutations and a high frequency of amplifications of not only MDM2 and CDK4 but also other genes. Potential driver mutations were found in only six (11{\%}) samples; however, gene amplification events (other than MDM2 and CDK4 amplification) were identified in 30 (54{\%}) samples. Receptor tyrosine kinase (RTK) genes in particular were amplified in 18 (32{\%}) samples. In addition, growth of a WDLPS cell line with IGF1R amplification was suppressed by simultaneous inhibition of CDK4 and IGF1R, using palbociclib and NVP-AEW541, respectively. Combination therapy with CDK4 and RTK inhibitors may be an effective therapeutic option for WDLPS/DDLPS patients with RTK gene amplification.",
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AU - Shiotani, Bunsyo

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AU - Fujimoto, Hiroyuki

AU - Chuman, Hirokazu

AU - Morioka, Hideo

AU - Matsumoto, Morio

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AU - Kubo, Takashi

AU - Kato, Mamoru

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AU - Kawai, Akira

AU - Kondo, Tadashi

AU - Ichikawa, Hitoshi

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