Identification of the mechanisms underlying tumorigenesis by oncogenic tyrosine kinases

• Project/Area Number: 16K21746
• Research Category: Fund for the Promotion of Joint International Research (Home-Returning Researcher Development Research)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology
• Research Institution: National Cancer Center Japan
• Principal Investigator: Kobayashi Susumu 国立研究開発法人国立がん研究センター, 先端医療開発センター, 分野長 (70792836)
• Co-Investigator(Kenkyū-buntansha): 犬塚 博之 東北大学, 歯学研究科, 准教授 (20335863)
• Project Period (FY): 2018 – 2021
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥56,290,000 (Direct Cost: ¥43,300,000、Indirect Cost: ¥12,990,000)
• Keywords: チロシンキナーゼ / 肺癌 / EGFR / 薬剤耐性 / 肺がん / β-catenin / チロシンキナーゼ阻害薬 / シグナル伝達

Outline of Final Research Achievements

The development of EGFR tyrosine kinase inhibitors revolutionized treatment of advanced/metastatic non-small-cell lung cancer with the EGFR mutations. However, resistance emerges over time in most patients who initially respond positively. Therefore, development of novel therapies to prevent and/or overcome resistance is required. We have demonstrated that β-catenin is phosphorylated in tumors harboring EGFR mutations, which induces BCL-xL expression and increases tumor cell survival through TBX5 transactivation. We believe that inhibition of theβ-catenin-TBX5-BCL-xL will overcome resistance to EGFR inhibitors and provide better prognosis for lung cancer patients with the EGFR mutations.

Academic Significance and Societal Importance of the Research Achievements

非小細胞肺癌におけるEGFR遺伝子活性型変異の発見とEGFRチロシンキナーゼ阻害薬の導入は、固形癌治療における分子標的療法の有効性を示した。しかし、治療開始時の劇的な効果にもかかわらず、ほぼすべての患者で再発が認められ、進行性非小細胞肺癌の完全治癒には至っていない。本研究は、細胞株、実験動物、患者検体を用いてEGFR阻害薬に対する耐性機構の一部の解明と、その克服法を示したという点で、極めて学術的・社会的意義の大きい研究であると考える。今後、実際の臨床応用を見据えたさらなる研究が必要である。

Research Products

• [Int'l Joint Research] Beth Israel Deaconess Medical Center/New York University(米国)
• [Int'l Joint Research] National University of Singapore(シンガポール)
• [Int'l Joint Research] Beth Israel Deaconess Medical Center/New York University(米国)
• [Int'l Joint Research] National University of Singapore(シンガポール)
• [Int'l Joint Research] Beth Israel Deaconess Medical Center（米国）
• [Journal Article] HSP90 inhibition overcomes EGFR amplification-induced resistance to third-generation EGFR-TKIs (2021)
  • Author(s): Watanabe S, Goto Y, Yasuda H, Kohno T, Motoi N, Ohe Y, Nishikawa H, Kobayashi SS, Kuwano K, Togashi Y.
  • Journal Title: Thoracic Cancer Volume: 12 Issue: 5 Pages: 631-42
  • DOI: 10.1111/1759-7714.13839
  • Peer Reviewed / Open Access
• [Journal Article] Alternative splicing of APOBEC3D generates functional diversity and its role as a DNA mutator (2020)
  • Author(s): Takei Hisashi、Fukuda Hirofumi、Pan Gilbert、Yamazaki Hiroyuki、Matsumoto Tadahiko、Kazuma Yasuhiro、Fujii Masanori、Nakayama Sohei、Kobayashi Ikei S.、Shindo Keisuke、Yamashita Riu、Shirakawa Kotaro、Takaori-Kondo Akifumi、Kobayashi Susumu S.
  • Journal Title: International Journal of Hematology Volume: 112 Issue: 3 Pages: 395-408
  • DOI: 10.1007/s12185-020-02904-y
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Long-read sequencing for non-small-cell lung cancer genomes (2020)
  • Author(s): Sakamoto Y, Xu L, Seki M, Yokoyama TT, Kasahara M, Kashima Y, Ohashi A, Shimada Y, Motoi N, Tsuchihara K, Kobayashi SS, Kohno T, Shiraishi Y, Suzuki A, Suzuki Y.
  • Journal Title: Genome Res Volume: 30 Issue: 9 Pages: 1243-57
  • DOI: 10.1101/gr.261941.120
  • Peer Reviewed / Open Access
• [Journal Article] Clinical Benefit of Tyrosine Kinase Inhibitors in Advanced Lung Cancer with EGFR-G719A and Other Uncommon EGFR Mutations. (2020)
  • Author(s): Sehgal K, Rangachari D, VanderLaan PA, Kobayashi SS, Costa DB
  • Journal Title: Oncologist Volume: 26 Issue: 4 Pages: 281-287
  • DOI: 10.1002/onco.13537
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Osimertinib Plus Savolitinib Is Mediated by MET-D1228 and MET-Y1230 Mutations in EGFR-Mutated MET-Amplified Lung Cancer (2020)
  • Author(s): Piper-Vallillo AJ, Halbert BT, Rangachari D, Kobayashi SS, Costa DB.
  • Journal Title: JTO Clinical and Research Reports Volume: 1 Pages: 100071-100071
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Combination treatment with a PI3K/Akt/mTOR pathway inhibitor overcomes resistance to anti-HER2 therapy in PIK3CA-mutant HER2-positive breast cancer cells (2020)
  • Author(s): Fujimoto Yumi、Morita Tomoko Yamamori、Ohashi Akihiro、Haeno Hiroshi、Hakozaki Yumi、Fujii Masanori、Kashima Yukie、Kobayashi Susumu S.、Mukohara Toru
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 21762-21762
  • DOI: 10.1038/s41598-020-78646-y
  • Peer Reviewed / Open Access
• [Journal Article] Preclinical characterization of mobocertinib highlights the putative therapeutic window of this novel EGFR inhibitor to EGFR exon 20 insertion mutations (2020)
  • Author(s): Vasconcelos PENS, Kobayashi IS, Kobayashi SS, Costa DB
  • Journal Title: JTO Clin Res Rep Volume: 2 Issue: 3 Pages: 100105-100105
  • DOI: 10.1016/j.jtocrr.2020.100105
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Molecular dynamics simulation-guided drug sensitivity prediction for lung cancer with rare EGFR mutations (2019)
  • Author(s): Ikemura S, Yasuda H, Matsumoto S, Kamada M, Hamamoto J, Masuzawa K, Kobayashi K, Manabe T, Arai D, Nakachi I, Kawada I, Ishioka K, Nakamura M, Namkoong H, Naoki K, Ono F, Araki M, Kanada R, Ma B, Hayashi Y, Mimaki S, Yoh K, Kobayashi SS, Kohno T, Okuno Y, Goto K, Tsuchihara K, Soejima K.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: Epub ahead of print Issue: 20 Pages: 10025-10030
  • DOI: 10.1073/pnas.1819430116
  • NAID: 120006799239
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Styryl quinazolinones and its ethynyl derivatives induce myeloid differentiation (2019)
  • Author(s): Radhakrishnan S, Syed R, Takei H, Kobayashi IS, Nakamura E, Sultana F, Kamal A, Tenen DG, Kobayashi SS.
  • Journal Title: Bioorg Med Chem Lett. Volume: 29 Issue: 16 Pages: 2286-2289
  • DOI: 10.1016/j.bmcl.2019.06.024
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Brief Report : EGFR-mutated lung cancers resistant to osimertinib through EGFR-C797S respond to 1st generation reversible EGFR inhibitors but eventually acquire EGFR-T790M/C797S in preclinical models and clinical samples (2019)
  • Author(s): Rangachari D, To C, Shpilsky JE, VanderLaan PA, Kobayashi SS, Mushajiang M, Lau CJ, Paweletz CP, Oxnard GR, Jänne PA, Costa DB
  • Journal Title: J Thorac Oncol. Volume: 14 Issue: 11 Pages: 1995-2002
  • DOI: 10.1016/j.jtho.2019.07.016
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] TAS6417/CLN-081 Is a Pan-Mutation-Selective EGFR Tyrosine Kinase Inhibitor with a Broad Spectrum of Preclinical Activity against Clinically Relevant EGFR Mutations. (2019)
  • Author(s): Udagawa H, Hasako S, Ohashi A, Fujioka R, Hakozaki Y, Shibuya M, Abe N, Komori T, Haruma T, Terasaka M, Fujita R, Hashimoto A, Funabashi K, Yasuda H, Miyadera K, Goto K, Costa DB, Kobayashi SS.
  • Journal Title: Mol Cancer Res Volume: 17(11) Issue: 11 Pages: 2233-2243
  • DOI: 10.1158/1541-7786.mcr-19-0419
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Effects of gefitinib treatment on cellular uptake of extracellular vesicles in EGFR-mutant non-small cell lung cancer cells (2019)
  • Author(s): Takenaka Tomoya、Nakai Shinya、Katayama Miku、Hirano Mami、Ueno Natsumi、Noguchi Kosuke、Takatani-Nakase Tomoka、Fujii Ikuo、Kobayashi Susumu S.、Nakase Ikuhiko
  • Journal Title: International Journal of Pharmaceutics Volume: 572 Pages: 118762-118762
  • DOI: 10.1016/j.ijpharm.2019.118762
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Transcription factor-based therapies for acute myeloid leukemia (2018)
  • Author(s): 小林 進、武井 寿史
  • Journal Title: Rinsho Ketsueki Volume: 59 Issue: 7 Pages: 922-931
  • DOI: 10.11406/rinketsu.59.922
  • NAID: 130007430209
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Styryl Quinazolinones as Potential Inducers of Myeloid Differentiation via Upregulation of C/EBP α (2018)
  • Author(s): Sridhar R, Takei H, Syed R, Kobayashi IS, Hui LB, Kamal A, Tenen DG, Kobayashi SS
  • Journal Title: Molecules Volume: 23 Issue: 8 Pages: 1938-1938
  • DOI: 10.3390/molecules23081938
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Activity of brigatinib in the setting of alectinib resistance mediated by ALK-I1171S in ALK rearranged lung cancer. (2018)
  • Author(s): Sehgal K, Peters MLB, VanderLaan PA, Rangachari D, Kobayashi SS, Costa DB.
  • Journal Title: Journal of Thoracic Oncology Volume: 23 Issue: 1 Pages: e1-e3
  • DOI: 10.1016/j.jtho.2018.06.020
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] EGFR exon 20 insertion mutations display sensitivity to Hsp90 inhibition in preclinical models and lung adenocarcinomas (2018)
  • Author(s): Jorge S, Lucena-Araujo AR, Yasuda H, Piotrowska Z, Oxnard GR, Rangachari D, Huberman M, Sequist LV, Kobayashi SS, Costa DB
  • Journal Title: Clin Cancer Res Volume: 24 Issue: 24 Pages: 6548-6555
  • DOI: 10.1158/1078-0432.ccr-18-1541
  • Peer Reviewed / Int'l Joint Research
• [Presentation] A novel germline mutation in the non-coding region of BRCA2, c.-40+1 G>A, is associated with hereditary breast cancer. (2020)
  • Author(s): Yumi Hakozaki, Yumi Fujimoto, Susumu S. Kobayashi, Mineko Ushiama, Yumie Hiraoka, Kenichi Harano, Takahiro Kogawa, Satoshi Fujii, Takeshi Kuwata, Teruhiko Yoshida, Akihiro Ohashi and Toru Mukohara
  • Organizer: AACR
  • Int'l Joint Research
• [Presentation] Multiomics approaches to clarify adaptive mechanisms of cancer cells to antiproliferative effects by chromosomal instability (2020)
  • Author(s): Tomoko Y. Morita, Hiroshi Haeno, Hideki Makinoshima, Ayako Suzuki, Susumu S. Kobayashi, and Akihiro Ohashi.
  • Organizer: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics
  • Int'l Joint Research
• [Presentation] Overview of drug resistance to TKI (2020)
  • Author(s): 小林 進
  • Organizer: 第61回日本肺癌学会
  • Invited
• [Presentation] Multiple modalities of single cell analyses to evaluate the tumor microenvironment in clinical specimens (2019)
  • Author(s): Yukie Kashima, Shota Fukuoka, Yosuke Togashi, Takahiro Kamada, Ayako Suzuki, Yoshiaki Nakamura, Kohei Shitara, Akihiro Ohashi, Taku Yoshida, Naofumi Taoka, Tatsuya Kawase, Teiji Wada, Kocihiro Inaki, Masataka Chihara, Yutaka Suzuki, Katsuya Tsuchihara, Susumu S Kobayashi, Hiroyoshi Nishikawa, Toshihiko Doi.
  • Organizer: AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics
  • Int'l Joint Research
• [Presentation] Met/Rorl-β-catenin-Bcl-xL axis contributes to the emergence of drug-tolerant cells that evolve into resistant tumors in EGFR-mutant lung cancer (2019)
  • Author(s): Masanori Fujii, Sohei Nakayama, Naoki Akanuma, Gilbert Pan, Ikei S. Kobayashi, Hisashi Takei, Kohei Shimizu, Mariko Ando, Eunyoung Heo, Carol Gergis, Hiroyuki Inuzuka, Wenyi Wei, Daniel B. Costa, and Susumu S. Kobayashi
  • Organizer: AACR Annual Meeting
  • Int'l Joint Research
• [Presentation] Preclinical evaluation of TAS6417 as a highly effective, pan-mutation-selective EGFR tyrosine kinase inhibitor (2019)
  • Author(s): Hibiki Udagawa, Shinichi Hasako, Akihiro Ohashi, Naomi Abe, Tomonori Haruma, Toshiharu Komori, Miki Terasaka, Ryoto Fujita, Kaoru Funabashi, Hiroyuki Yasuda, Kazutaka Miyadera, Koichi Goto, Daniel B. Costa and Susumu S. Kobayashi
  • Organizer: AACR Annual Meeting
  • Int'l Joint Research
• [Presentation] 治療抵抗性腫瘍の治療開発 (2019)
  • Author(s): 小林 進
  • Organizer: 日本臨床腫瘍学会
  • Invited
• [Presentation] Tumor Heterogeneity and Implications to Treatment Strategy with EGFR TKIs (2019)
  • Author(s): 小林 進
  • Organizer: 日本肺癌学会北海道支部会
  • Invited
• [Presentation] Resistance to EGFR Tyrosine Kinase Inhibitors (2019)
  • Author(s): Susumu S. Kobayashi
  • Organizer: The 34th Nagoya International Cancer Treatment Symposium
  • Invited
• [Presentation] Met/Rorl-β-catenin-Bcl-xL axis contributes to the emergence of drug-tolerant cells that evolve into resistant tumors in EGFR-mutant lung cancer. (2019)
  • Author(s): Masanori Fujii, Sohei Nakayama, Naoki Akanuma, Gilbert Pan, Ikei S, Kobayashi, Hisashi Takei, Kohei Shimizu, Mariko Ando, Eunyoung Heo, Carol Gergis, Hiroyuki Inuzuka, Wenyi Wei, Daniel B. Costa, Susumu S. KObayashi.
  • Organizer: American Association for Cancer Research
  • Int'l Joint Research
• [Presentation] Mechanisms and strategies to overcome resistance to tyrosine kinase inhibitors in lung cancer (2018)
  • Author(s): Susumu S. Kobayashi
  • Organizer: 日本がん学会
  • Invited
• [Book] 医学の歩み (2020)
  • Author(s): 小林 進
  • Total Pages: 5
  • Publisher: 医歯薬出版
• [Book] 血液内科 (2020)
  • Author(s): 江口 基紀、小林 進、南 陽介
  • Total Pages: 6
  • Publisher: 科学評論社
• [Remarks] 申請者のホームページ
  • URL: https://www.ncc.go.jp/jp/epoc/division/translational_genomics/kashiwa/index.html