Screening of biomarkers to predict the drug efficacy based on translation profiling

• Project/Area Number: 16K18444
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor diagnostics
• Research Institution: National Institute of Health Sciences
• Principal Investigator: Tsukumo Yoshinori 国立医薬品食品衛生研究所, 遺伝子医薬部, 主任研究官 (40469630)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2017: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 肺がん / バイオマーカー / EGFR / 分子標的薬 / 翻訳 / リボソームプロファイリング / ゲノム編集 / L858R / EGFR阻害薬 / 癌 / 翻訳調節 / CRISPR-Cas9

Outline of Final Research Achievements

EGFR inhibitors become highly effective molecular targeted drugs if the tumor harbors EGFR-activating mutation such as L858R or del 19. Therefore, the EGFR mutation test is essential for treatment decision. Currently, direct sampling of tumor tissue is being performed in many cases. However, such invasive method is accompanied with pain and the risk of complications including spreading or adhesion of tumor tissue. In this research, we aimed to identify novel biomarkers applicable for low-invasive approach. Using genome editing, we succeeded in establishment of new cell lines harboring EGFR-L858R mutation. We performed screening of mRNAs which are translationally upregulated or down regulated in EGFR mutation-dependent manner using the technique called ribosome profiling. Finally we found several candidates including secreted proteins and exosome components.

Research Products

• [Journal Article] Current and Future Issues of Companion Diagnostics (2017)
  • Author(s): 築茂 由則, 鈴木 孝昌, 内藤 幹彦
  • Journal Title: Regulatory Science of Medical Products Volume: 7 Issue: 2 Pages: 71-80
  • DOI: 10.14982/rsmp.7.71
  • NAID: 130007040567
  • ISSN: 2185-7113, 2189-0447
  • Peer Reviewed
• [Journal Article] Translation control during prolonged mTORC1 inhibition mediated by 4E-BP3. (2016)
  • Author(s): Tsukumo Y, Alain T, Fonseca BD, Nadon R, Sonenberg N.
  • Journal Title: Nat Commun Volume: 7 Issue: 1 Pages: 11776-11776
  • DOI: 10.1038/ncomms11776
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transcriptional induction of 4E-BP3 prolongs translation repression. (2016)
  • Author(s): Tsukumo Y, Sonenberg N, Alain T.
  • Journal Title: Cell Cycle Volume: 15 Issue: 24 Pages: 3325-3326
  • DOI: 10.1080/15384101.2016.1224786
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Control of embryonic stem cell self-renewal and differentiation via coordinated alternative splicing and translation of YY2. (2016)
  • Author(s): Tahmasebi S, Jafarnejad SM, Tam IS, Gonatopoulos-Pournatzis T, Matta-Camacho E, Tsukumo Y, Yanagiya A, Li W, Atlasi Y, Caron M, Braunschweig U, Pearl D, Khoutorsky A, Gkogkas CG, Nadon R, Bourque G, Yang XJ, Tian B, Stunnenberg HG, Yamanaka Y, Blencowe BJ, Giguere V, Sonenberg N.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 113 Issue: 44 Pages: 12360-12367
  • DOI: 10.1073/pnas.1615540113
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Establishment of EGFR L858R-knock-in cells using a genome editing technology and their EGFR-TKI sensitivity (2017)
  • Author(s): 築茂 由則, 鈴木 孝昌, 内藤 幹彦
  • Organizer: 日本癌学会学術総会