Development of synthetic lethality on lung cancer harboring KRAS mutation

• Project/Area Number: 16K10670
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory surgery
• Research Institution: Tohoku University
• Principal Investigator: Sakurada Akira 東北大学, 加齢医学研究所, 准教授 (60360872)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 肺癌 / 腺癌 / KRAS / 合成致死 / K-RAS / KAS

Outline of Final Research Achievements

Synthetic lethality on lung cancer cells harboring KRAS gene mutation was tested. p190RhoGAP was assumed as one target and additional targets were intended to identify by using isogenic cell culture model in combination with siRNA library screening. As integration of autofluorescent gene was unstable, we switched isogenic model to combination of inhibitors. We confirmed that inhibition of Src, a upstream regulator of p190RhoGAP, strongly donuregulates p190RhoGAP activity. Then, we identified that Stat3 was upregulated and contributed for cell survival after stale knock down of p190RhoGAP. We demonstarated that simultaneous inhibiton ofStat3 and SRC synergistically supress cell proliferation of A549 cell.

Academic Significance and Societal Importance of the Research Achievements

今回、KRAS遺伝子変異を有する肺癌細胞株を用いた実験で、SRC阻害薬とSTAT3の阻害薬がいずれも増殖抑制効果を示すこと、また、両者を併用すると相乗的で強力な細胞増殖抑制効果が得られることを示した。肺癌の分子標的治療は進歩しているが、これまでKRAS遺伝子変異を有する肺癌に対しては有効な治療法が確立しておらず、今回の結果は新たな治療の可能性を示すものと考えられる。

Research Products

• [Journal Article] Growth inhibition of KRAS and EGFR mutant lung adenocarcinoma by cosuppression of STAT3 and the SRC/ARHGAP35 axis (2018)
  • Author(s): Onodera K, Sakurada A, Notsuda H, Watanabe T, Matsuda Y, Noda M, Endo C, Okada Y
  • Journal Title: Oncology Rep Volume: 40 Pages: 1761-1768
  • DOI: 10.3892/or.2018.6536
  • Peer Reviewed
• [Journal Article] Epidermal Growth Factor Receptor Mutation as a Risk Factor for Recurrence in Lung Adenocarcinoma (2018)
  • Author(s): Hayasaka Kazuki、Shiono Satoshi、Matsumura Yuki、Yanagawa Naoki、Suzuki Hiroyuki、Abe Jiro、Sagawa Motoyasu、Sakurada Akira、Katahira Masato、Takahashi Satomi、Endoh Makoto、Okada Yoshinori
  • Journal Title: The Annals of Thoracic Surgery Volume: 105 Issue: 6 Pages: 1648-1654
  • DOI: 10.1016/j.athoracsur.2018.01.052
  • Peer Reviewed
• [Journal Article] Matched-pair analysis of a multi-institutional cohort reveals that epidermal growth factor receptor mutation is not a risk factor for postoperative recurrence of lung adenocarcinoma (2017)
  • Author(s): Matsumura Yuki、Suzuki Hiroyuki、Ohira Tetsuya、Shiono Satoshi、Abe Jiro、Sagawa Motoyasu、Sakurada Akira、Katahira Masato、Machida Yuichiro、Takahashi Satomi、Okada Yoshinori
  • Journal Title: Lung Cancer Volume: 114 Pages: 23-30
  • DOI: 10.1016/j.lungcan.2017.09.003
  • Peer Reviewed
• [Journal Article] A prospective 5-year follow-up study after limited resection for lung cancer with ground-glass opacity (2017)
  • Author(s): Sagawa Motoyasu、Oizumi Hiroyuki、Suzuki Hiroyuki、Uramoto Hidetaka、Usuda Katsuo、Sakurada Akira、Chida Masayuki、Shiono Satoshi、Abe Jiro、Hasumi Tohru、Sato Masami、Sato Nobuyuki、Shibuya Jotaro、Deguchi Hiroyuki、Okada Yoshinori
  • Journal Title: Eur J Cardiothorac Surg Volume: 53 Issue: 4 Pages: 849-856
  • DOI: 10.1093/ejcts/ezx418
  • Peer Reviewed / Open Access
• [Journal Article] Cytotoxicity of natural killer cells activated through NKG2D contributes to the development of bronchiolitis obliterans in a murine heterotopic tracheal transplant model. (2017)
  • Author(s): Kawakami T, Ito K, Matsuda Y, Noda M, Sakurada A, Hoshikawa Y, Okada Y, Ogasawara K.
  • Journal Title: Am J Transplant. Volume: 印刷中 Issue: 9 Pages: 2338-2349
  • DOI: 10.1111/ajt.14257
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] SOX2 and Rb1 in esophageal small-cell carcinoma: their possible involvement in pathogenesis (2017)
  • Author(s): Ishida H, Kasajima A, Kamei T, Miura T, Oka N, Yazdani S, Ozawa Y, Fujishima F, Sakurada A, Nakamura Y, Tanaka Y, Kurosumi M, Ishikawa Y, Okada Y, Ohuchi N, Sasano H
  • Journal Title: Mod Pathol Volume: 30 Issue: 5 Pages: 660-671
  • DOI: 10.1038/modpathol.2016.222
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Serum β-hCG as an Indicator of Recurrence After the Complete Resection of a Malignant Solitary Fibrous Tumor of the Pleura. (2016)
  • Author(s): Yabuki H, Sakurada A, Niikawa H, Notsuda H, Endo C, Matsuda Y, Noda M, Saito R, Yamashita S, Arai Y, Okada Y.
  • Journal Title: Ann Thorac Surg Volume: 102 Issue: 6 Pages: e551-e553
  • DOI: 10.1016/j.athoracsur.2016.05.061
  • Peer Reviewed
• [Presentation] Uncommon EGFR mutations as a worse prognostic factor for surgically resected lung adenocarcinoma (2018)
  • Author(s): Hayasaka K, Shiono S, Matsumura Y, Suzuki H, Yanagawa N, Abe J, Sagawa M, Sakurada A, Katahira M, Takahashi S, Endoh M, Okada Y.
  • Organizer: International Association for Study of Lung Cancer 19th World Conference on Lung Cancer
  • Int'l Joint Research
• [Presentation] 開胸により初めて判明する胸膜病変のリスク因子について (2017)
  • Author(s): 桜田 晃、星 史彦、江場俊介、大石 久、松田安史、佐渡 哲、野田雅史、岡田克典
  • Organizer: 日本肺癌学会総会
• [Presentation] Cosuppression of Stat3 and Src/p190RhoGAP leads synergistic growth inhibition in KRAS mutant lung adenocarcinoma (2016)
  • Author(s): Ken Onodera, Akira Sakurada, Hirotsugu Notsuda, Tatsuaki Watanabe, Yasushi Matsuda, Masafumi Noda, Yasushi Hoshikawa, Yoshinori Okada
  • Organizer: American Thoracic Society 2016 International Conference
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2016-05-13
  • Int'l Joint Research