Develop novel therapeutics against KRAS mutant cancer by regulating PI3K and ERK signal(Fostering Joint International Research)

• Project/Area Number: 15KK0303
• Research Category: Fund for the Promotion of Joint International Research (Fostering Joint International Research)
• Allocation Type: Multi-year Fund
• Research Field: Tumor therapeutics
• Research Institution: Aichi Cancer Center Research Institute (2017-2019); Kanazawa University (2015-2016)
• Principal Investigator: Ebi Hiromichi 愛知県がんセンター(研究所), がん標的治療TR分野, 分野長 (00645145)
• Project Period (FY): 2016 – 2019
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥14,300,000 (Direct Cost: ¥11,000,000、Indirect Cost: ¥3,300,000)
• Keywords: KRAS / 上皮間葉移行 / シグナル伝達 / フィードバック機構 / MEK / SHP2 / 受容体 / BRAF / MAPK / スクリーニング / 癌 / トランスレーショナルリサーチ

Outline of Final Research Achievements

We identified epithelial-to-mesenchymal transition (EMT) rewires the expression of receptor tyrosine kinases (RTKs), leading to differential feedback activation of the ERK pathway following MEK inhibition in KRAS mutant cancer. In epithelial-like cancers, this feedback was attributed to ERBB3-mediated activation of MEK and AKT. In contrast, in mesenchymal-like cancers, FGFR1 was dominantly expressed but suppressed by the negative regulator Sprouty proteins; MEK inhibition led to repression of SPRY4 and subsequent FGFR1-mediated reactivation of MEK and AKT. Therapeutically, the combination of a MEK inhibitor with respective RTK inhibitors induced cell death in vitro and tumor regressions in vivo. We also functionally characterized BRAF mutant cancers by an international collaboration. Collectively, we have established the rationale and a therapeutic approach to treat KRAS-mutant lung cancers based on EMT status, and BRAF mutant cancers based on its functional classification.

Academic Significance and Societal Importance of the Research Achievements

KRAS変異腫瘍が上皮間葉移行状態に基づきサブタイプ分類が可能なこと、またサブタイプによりシグナル伝達形式が異なることが明らかとなったことは、KRAS変異腫瘍の分子生物学的理解に加え、サブタイプ別の治療開発につながる可能性がある。またKRAS G12C阻害薬については現在第III相試験が行われており、感受性・耐性規定因子の同定により、阻害薬に効果の期待できる患者の同定や新たな治療開発につながる可能性を有する。本課題を発展する形で開始されたBRAF変異腫瘍に対する個別化治療法開発については、BRAF変異腫瘍の機能別分類と、分類ごとの治療法提唱ができたため、患者治療に役立つことが期待される。

Research Products

• [Int'l Joint Research] ノバルティスバイオメディカル研究所(米国) (2018)
  • Year and Date: 2018-03-28
• [Journal Article] PTEN loss mediates clinical cross-resistance to CDK4/6 and PI3Kalpha inhibitors in breast cancer. (2020)
  • Author(s): Costa C, Wang Y, Ly A, Hosono Y, Ellen M, Walmsley CS, Huynh T, Healy C, Peterson R, Yanase S, Jakubik CT, Henderson LE, Damon LJ, Timonina D, Sanidas I, Pinto CJ, Mino-Kenudson M, Stone JR, Dyson NJ, Ellisen LW, Bardia A, Ebi H, Benes CH, Engelman JA and Juric D.
  • Journal Title: Cancer Discovery Volume: 10 Issue: 1 Pages: 72-85
  • DOI: 10.1158/2159-8290.cd-18-0830
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Response to Anti-EGFR Therapy in Patients with BRAF non-V600-Mutant Metastatic Colorectal Cancer. (2019)
  • Author(s): 20.Yaeger R, Kotani D, Mondaca S, Parikh AR, Bando H, Van Seventer EE, Taniguchi H, Zhao H, Thant CN, de Stanchina E, Rosen N, Corcoran RB, Yoshino T, Yao Z and Ebi H.
  • Journal Title: Clinical Cancer Research Volume: 25 Issue: 23 Pages: 7089-7097
  • DOI: 10.1158/1078-0432.ccr-19-2004
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] The ADAM17 Protease Promotes Tobacco Smoke Carcinogen-induced Lung Tumourigenesis. (2019)
  • Author(s): Saad MI, McLeod L, Yu L, Ebi H, Ruwanpura S, Sagi I, Rose-John S and Jenkins BJ.
  • Journal Title: Carcinogenesis Volume: pii: bgz123 Issue: 4 Pages: 1-12
  • DOI: 10.1093/carcin/bgz123
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] ADAM17 selectively activates the IL‐6 trans‐signaling/ERK MAPK axis in KRAS‐addicted lung cancer (2019)
  • Author(s): Saad MI, Alhayyani S, McLeod L, Liang Yu L, Alanazi M, Deswaerte V, Tang K, Jarde T, Smith JA, Prodanovic Z, Tate MD, Balic JJ, Watkins DM, Cain JE, Bozinovski S, Algar E, Kohmoto T, Ebi H, Ferlin W, Garbers C, Ruwanpura S, Sagi I, Rose-John S, Jenkins BJ
  • Journal Title: EMBO Molecular Medicine Volume: 11 Issue: 4
  • DOI: 10.15252/emmm.201809976
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ALK Expression in Small Cell Lung Cancer (2019)
  • Author(s): Kondoh Chiaki、Horio Yoshitsugu、Hayashi Yuko、Ebi Hiromichi、Hida Toyoaki、Hasegawa Yoshinori、Yatabe Yasushi
  • Journal Title: Histopathology Volume: in press Issue: 1 Pages: 20-28
  • DOI: 10.1111/his.13842
  • Peer Reviewed
• [Journal Article] Evaluation of ALK fusion newly identified in colon cancer by a comprehensive genomic analysis. (2019)
  • Author(s): Hosono Y, Masuishi T, Mitani S, Yamaguchi R, Kato S, Yoshino T, Ebi H.
  • Journal Title: JCO Precision Oncology Volume: 3 Issue: 3 Pages: 1-4
  • DOI: 10.1200/po.19.00268
  • Peer Reviewed
• [Journal Article] Increased Synthesis of MCL-1 Protein Underlies Initial Survival of EGFR-Mutant Lung Cancer to EGFR Inhibitors and Provides a Novel Drug Target (2018)
  • Author(s): Song KA, Hosono Y, Turner C, Jacob S, Lochmann TL, Murakami Y, Patel NU, Ham J, Hu B, Powell KM, Coon CM, Windle B, Oya Y, Koblinski JE, Harada H, Leverson JD, Souers AJ, Hata AN, Boikos SA, Yatabe Y, Ebi H, Faber AC
  • Journal Title: Clinical Cancer Research Volume: 24 Issue: 22 Pages: 5658-5672
  • DOI: 10.1158/1078-0432.ccr-18-0304
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Japanese Society of Medical Oncology Clinical Guidelines: Molecular Testing for Colorectal Cancer Treatment, Third Edition (2018)
  • Author(s): Yamazaki Kentaro、Taniguchi Hiroya、Yoshino Takayuki、Akagi Kiwamu、Ishida Hideyuki、Ebi Hiromichi、Nakatani Kaname、Muro Kei、Yatabe Yasushi、Yamaguchi Kensei、Tsuchihara Katsuya
  • Journal Title: Cancer Science Volume: 109 Issue: 6 Pages: 2074-2079
  • DOI: 10.1111/cas.13617
  • Peer Reviewed
• [Journal Article] Distinct dependencies on receptor tyrosine kinases in the regulation of MAPK signaling between BRAF V600E and non-V600E mutant lung cancers (2018)
  • Author(s): Kotani Hiroshi、Adachi Yuta、Kitai Hidenori、Tomida Shuta、Bando Hideaki、Faber Anthony C.、Yoshino Takayuki、Voon Dominic C.、Yano Seiji、Ebi Hiromichi
  • Journal Title: Oncogene Volume: 37 Issue: 13 Pages: 1775-1787
  • DOI: 10.1038/s41388-017-0035-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] RAS/MAPK系に対する治療開発と課題 (2018)
  • Author(s): 衣斐寛倫
  • Journal Title: 実験医学 Volume: 36 Pages: 2530-2534
• [Journal Article] KRAS遺伝子変異肺がんに対する分子標的治療 (2018)
  • Author(s): 衣斐寛倫
  • Journal Title: 最新医学 Volume: 73 Pages: 983-988
  • NAID: 40021632024
• [Journal Article] Epithelial-to-Mesenchymal Transition Antagonizes Response to Targeted Therapies in Lung Cancer by Suppressing BIM (2017)
  • Author(s): Song Kyung-A、Ebi Hiromichi、et al. (30人中28番目）
  • Journal Title: Clinical Cancer Research Volume: 24 Issue: 1 Pages: 197-208
  • DOI: 10.1158/1078-0432.ccr-17-1577
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Key roles of EMT for adaptive resistance to MEK inhibitor in KRAS mutant lung cancer (2017)
  • Author(s): Kitai Hidenori、Ebi Hiromichi
  • Journal Title: Small GTPases Volume: 8 Issue: 3 Pages: 172-176
  • DOI: 10.1080/21541248.2016.1210369
  • Peer Reviewed
• [Presentation] Targeting cancers with aberrant MAPK signal (2019)
  • Author(s): Hiromichi Ebi
  • Organizer: The 24th JFCR－ISCC International Meeting
  • Int'l Joint Research / Invited
• [Presentation] Overcome Resistance by Regulating Feedback Signaling Pathway (2019)
  • Author(s): Hiromichi Ebi
  • Organizer: 名古屋国際癌治療シンポジウム
  • Int'l Joint Research / Invited
• [Presentation] MEK阻害薬に対する耐性機序 (2018)
  • Author(s): 衣斐寛倫
  • Organizer: 日本肺癌学会学術総会
  • Invited
• [Presentation] Intrinsic and acquired resistance to tumors aberrant MAPK signaling (2018)
  • Author(s): 衣斐寛倫
  • Organizer: 第77回日本癌学会学術総会
  • Invited
• [Presentation] Combination Therapies Targeting KRAS Mutant Lung Cancer. (2018)
  • Author(s): Hiromichi Ebi
  • Organizer: The 6th JCA-AACR Special Joint Conference
  • Int'l Joint Research / Invited
• [Presentation] MAPK変異腫瘍における分子標的治療薬耐性の解明と新規治療開発 (2017)
  • Author(s): 衣斐寛倫
  • Organizer: 第21回日本がん分子標的治療学会学術集会
  • Invited
• [Presentation] BRAF変異腫瘍におけるシグナル伝達系の違いを利用した新規治療戦略 (2017)
  • Author(s): 衣斐寛倫 小谷浩，足立雄太，矢野聖二
  • Organizer: 第76回日本癌学会学術総会
• [Book] 分子呼吸器病 (2017)
  • Author(s): 衣斐寛倫
  • Total Pages: 3
  • Publisher: 先端医学社