Synthetic lethal interaction of CDK inhibition and autophagy inhibition in human solid cancer cell lines

• Project/Area Number: 24501349
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Clinical oncology
• Research Institution: Juntendo University (2013-2014); Tohoku University (2012)
• Principal Investigator: SHUNSUKE Kato 順天堂大学, 医学(系)研究科(研究院), 教授 (40312657)
• Co-Investigator(Kenkyū-buntansha): KAKUDO Yuichi 東北大学, 加齢医学研究所, 助教 (10396484)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: オートファジー / CDK阻害剤 / 分子標的治療 / 大腸がん / 血管新生阻害 / 細胞周期停止 / 化学療法 / がん

Outline of Final Research Achievements

We revealed that CDK inhibitor induced autophagy in some, but not all, solid cancer cell lines. In the cell lines showing autophagy, which was induced by CDK inhibitor, the combination of CDK inhibitor and autophagy inhibition induced apoptosis. However, it did not induce apoptosis in the cell lines in which autophagy was not induced by CDK inhibitor. These findings indicate that the autophagy induced by CDK inhibitor mimics stress-induced autophagy in some solid cancer cell lines. The combination of a small-molecule CDK inhibitor involved in G1/S arrest and an autophagy inhibitor leads to a synthetic lethal interaction and could become a new antitumor strategy for solid tumors showing cytoprotective autophagy induced by small-molecule CDK inhibitors.

Research Products

• [Journal Article] High throughput RNAi screening identifies ID1 as a synthetic sick/lethal gene interacting with the common TP53 mutation R175H. (2014)
  • Author(s): Imai H, Kato S, Sakamoto Y, Kakudo Y, Shimodaira H, Ishioka C.
  • Journal Title: Oncol Rep. Volume: 31 Issue: 3 Pages: 1043-1050
  • DOI: 10.3892/or.2013.2953
  • Peer Reviewed
• [Journal Article] 抗VEGF経路抗体薬‐ベバシズマブ，アフリベルセプト，ラムシルマブ- (2014)
  • Author(s): 加藤俊介、塩野雅俊
  • Journal Title: 最新医学 Volume: 69 Pages: 400-406
• [Journal Article] Clinical usefulness of KRAS, BRAF, and PIK3CA mutations as predictive markers of cetuximab efficacy in irinotecan- and oxaliplatin-refractory Japanese patients with metastatic colorectal cancer. (2013)
  • Author(s): Soeda H, Shimodaira H, Watanabe M, Suzuki T, Gamoh M, Mori T, Komine K, Iwama N, Kato S, Ishioka C.
  • Journal Title: Int J Clin Oncol. Volume: 18 Issue: 4 Pages: 670-677
  • DOI: 10.1007/s10147-012-0422-8
  • Peer Reviewed
• [Journal Article] 分子標的治療薬（抗体薬） (2013)
  • Author(s): 加藤俊介
  • Journal Title: Modern Physician Volume: 33 Pages: 361-363
• [Journal Article] 消化器がんにおける血管新生阻害剤の役割 (2013)
  • Author(s): 加藤俊介
  • Journal Title: がん分子標的治療 Volume: 11 Pages: 119-126
• [Journal Article] Kawai, S., Kato, S., Imai, H., Okada, Y., Ishioka C. Suppression of FUT1 attenuates cell proliferation in HER2-overexpressing cancer cell line NCI-N87. (2013)
  • Author(s): Kawai S, Kato S, Imai H, Okada Y, Ishioka C.
  • Journal Title: Oncol Rep. Volume: 29 Issue: 1 Pages: 13-20
  • DOI: 10.3892/or.2012.2120
  • Peer Reviewed
• [Journal Article] 大腸がんに対する新しい分子標的薬（レゴラフェニブとアフリバセプト） (2013)
  • Author(s): 加藤俊介
  • Journal Title: 癌と化学療法 Volume: 40 Pages: 6-9
• [Journal Article] Multicenter Retrospective Study of 132 Patients with Unresectable Small Bowel Adenocarcinoma Treated with Chemotherapy (2012)
  • Author(s): Tsushima, T., Taguri, M., Honma, Y., Takahashi, H., Ueda, S., Nishina, T., Kawai, H., Kato, S., Morita, S., Boku, N
  • Journal Title: Oncologist Volume: 17 Pages: 1163-1170
  • Peer Reviewed
• [Journal Article] Safety Verification Trials of mFOLFIRI and Sequential IRIS + Bevacizumab as First- or Metastantic Colorectal Cancer in Japanese Patients (2012)
  • Author(s): Kato S, Andoh H, Gamoh M, Yamaguchi T, Murakawa T, Shimodaira H, Takahashi S, Mori T, Ohori H, Maeda S, Suzuki T, Kato S, Akiyama S, Sasaki Y, Yoshioka T, Ishioka C
  • Journal Title: Oncology Volume: 83 Issue: 2 Pages: 101-107
  • DOI: 10.1159/000339541
  • Peer Reviewed
• [Presentation] 切除不能進行再発胃がんの治療戦略 (2014)
  • Author(s): 加藤俊介
  • Organizer: 第12回日本臨床腫瘍学会
  • Place of Presentation: 福岡国際会議場（福岡）
  • Year and Date: 2014-07-17
  • Invited
• [Presentation] 希少がんに対する分子標的薬（軟部肉腫、GIST、NET) (2014)
  • Author(s): 加藤俊介
  • Organizer: 第18回日本がん分子標的治療学会学術集会
  • Place of Presentation: 仙台市情報・産業プラザ（仙台）
  • Year and Date: 2014-06-26
  • Invited
• [Presentation] オキザリプラチン（L-OHP)起因性蓄積性末梢知覚神経障害に対する休薬期間による改善効果に関する検討 (2014)
  • Author(s): 加藤俊介、蒲生真紀夫、下平秀樹、村川康子、天貝賢二、伊東重豪、添田 大司、二井谷友公、吉岡 孝志、石岡 千加史
  • Organizer: 第111回日本内科学会
  • Place of Presentation: 東京国際フォーラム（東京）
  • Year and Date: 2014-04-11
• [Presentation] Synthetic lethal interaction of CDK inhibition and autophagy inhibition in human solid cancer cell lines. (2013)
  • Author(s): Okada Y, Kato S, Sakamoto Y, Oishi T, Ishioka C.
  • Organizer: American Association for Cancer Research
  • Place of Presentation: Washington, USA
• [Presentation] 膵癌に対する分子標的薬―最近の動向 (2013)
  • Author(s): 加藤俊介
  • Organizer: 第21回日本消化器関連学会週間
  • Place of Presentation: 東京グランドプリンスホテル高輪
  • Invited
• [Presentation] 胞巣状肉腫に対してPazopanibが奏功した2例 (2013)
  • Author(s): 伊藤祝栄、加藤俊介、保坂正美、綿貫宗則、鈴木賢太郎、林耕宇、秋山聖子、高橋信、高橋雅信、添田大司、井上正広、城田英和、森隆弘、下平秀樹、石岡千加史
  • Organizer: 第51回日本癌治療学会学術集会
  • Place of Presentation: 京都
• [Presentation] Synthetic lethal interaction of CDK inhibition and autophagy inhibition in human solid cancer cell lines (2013)
  • Author(s): Okada Y, Kato S, Sakamoto Y, Oishi T, Ishioka C.
  • Organizer: AACR annual meeting 2013
  • Place of Presentation: Washington, USA
• [Presentation] CDK4阻害剤とオートファジー阻害の併用はアポトーシスを誘導する (2012)
  • Author(s): 岡田佳也，加藤俊介，大石隆之，坂本康寛，石岡千加史
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌