Tumor agonistic and tissue specific role of BRAF mutations in cancer

• Project/Area Number: 20H03542
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Aichi Cancer Center Research Institute
• 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): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2022: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2021: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2020: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
• Keywords: BRAF / mutation / molecular classification / クラス分類 / 獲得変異 / 機能解析 / tumor agonistic / サブタイプ / 個別化治療 / 臓器多様性 / BRAF変異 / tumor agonistic therapy

Outline of Research at the Start

BRAF変異腫瘍は、変異タンパクの機能により3種類に分類される。また、変異タンパクが果たす役割については、腫瘍の発生臓器により異なることが示唆されている。本研究では、これまでに報告されている変異のうち、機能が判明していないものについて機能解析を行う。そのうえで、各サブタイプについて国際共同研究により検体・患者由来ゼノグラフトを用いた解析を行い、臓器特異性の背景を解明する。最終的には、各変異に対し、臓器特異性に基づく有効な治療を提唱することが目的である。

Outline of Final Research Achievements

We performed functional analysis of 106 variants of BRAF with unknown function and identified 17 novel gain-of-function mutations. The reasons for the gain-of-function of these mutations were inferred from the protein sequence, structure, and interactions, and a predictive model of function was constructed. We also performed expression and pathway analyses of colorectal cancer cases with each BRAF mutation, which can be classified into three types based on their functions, and examined the effects of phenotypic differences on tumorigenesis. In addition, we focused on Class I mutant BRAF colorectal cancer and identified candidate molecules that could be responsible for resistance to currently approved inhibitors.

Academic Significance and Societal Importance of the Research Achievements

ゲノム医療特に包括的遺伝子プロファイリング検査が臨床導入され、近年BRAF変異が同定される機会が増えている。それらの多くは機能不明バリアントであることから、本研究により、機能不明バリアントの機能予測が可能になれば、患者の治療法選択に役立てることが可能である。また、BRAF Class 1変異（V600変異）大腸がんについては、現在抗EGFR抗体とBRAF阻害薬の併用療法がされているが、30%程度の患者に奏効するのみである。本研究ではパスウエイ解析の結果、Class 1変異が2種類に分類される結果が得られており、今後阻害薬の効果との関連を明らかにすることで、新たな治療法を提唱できる可能性がある。

Research Products

• [Int'l Joint Research] Virginia Commonwealth University/Memorial Sloan Kettering Cancer Center(米国)
• [Int'l Joint Research] Memorial Sloan Kettering Cancer Center(米国)
• [Journal Article] Drug-Tolerant Persister Cells After EGFR Tyrosine Kinase Inhibitor Treatment: Their Origin and the Influences From the Tumor Microenvironment (2023)
  • Author(s): Ebi Hiromichi
  • Journal Title: Journal of Thoracic Oncology Volume: 18 Issue: 4 Pages: 399-401
  • DOI: 10.1016/j.jtho.2022.12.010
  • Peer Reviewed
• [Journal Article] ARAF protein kinase activates RAS by antagonizing its binding to RASGAP NF1 (2022)
  • Author(s): Su W、Mukherjee R、Yaeger R、Son J、Xu J、Na N、Merna TN、Hechtman J、Paroder V、Lin M、Mattar M、Qiu J、Chang Q、Zhao H、Zhang J、Little M、Adachi Y、Han SW、Taylor BS.、Ebi H、Abdel-Wahab O、de Stanchina E、Rudin CM.、Janne PA.、McCormick F、Yao Z、Rosen N.
  • Journal Title: Molecular Cell Volume: 82 Issue: 13 Pages: 2443-2457.e7
  • DOI: 10.1016/j.molcel.2022.04.034
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] High-risk neuroblastoma with NF1 loss of function is targetable using SHP2 inhibition (2022)
  • Author(s): Cai J、Jacob S、Kurupi R、Dalton KM.、Coon C、Greninger P、Egan RK.、Stein GT.、Murchie E、McClanaghan J、Adachi Y、Hirade K、Dozmorov M、Glod J、Boikos SA.、Ebi H、Hao H、Caponigro G、Benes CH.、Faber AC.
  • Journal Title: Cell Reports Volume: 40 Issue: 4 Pages: 111095-111095
  • DOI: 10.1016/j.celrep.2022.111095
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] MAPK経路、がんゲノム医療時代の分子腫瘍学 (2022)
  • Author(s): 1.衣斐寛倫
  • Journal Title: 病理と臨床 Volume: 40 Pages: 092-095
• [Journal Article] Escaping KRAS: Gaining Autonomy and Resistance to KRAS Inhibition in KRAS Mutant Cancers (2021)
  • Author(s): Adachi Yuta、Kimura Ryo、Hirade Kentaro、Ebi Hiromichi
  • Journal Title: Cancers Volume: 13 Issue: 20 Pages: 5081-5081
  • DOI: 10.3390/cancers13205081
  • Peer Reviewed / Open Access
• [Journal Article] CIRCULATE‐Japan: Circulating tumor DNA?guided adaptive platform trials to refine adjuvant therapy for colorectal cancer (2021)
  • Author(s): Taniguchi Hiroya、Nakamura Yoshiaki、Kotani Daisuke、Yukami Hiroki、Mishima Saori、Sawada Kentaro、Shirasu Hiromichi、Ebi Hiromichi、Yamanaka Takeharu、Aleshin Alexey、Billings Paul R.、Rabinowitz Matthew、Oki Eiji、Takemasa Ichiro、Kato Takeshi、Mori Masaki、Yoshino Takayuki
  • Journal Title: Cancer Science Volume: 112 Issue: 7 Pages: 2915-2920
  • DOI: 10.1111/cas.14926
  • Peer Reviewed
• [Journal Article] TGF-β-dependent reprogramming of amino acid metabolism induces epithelial?mesenchymal transition in non-small cell lung cancers (2021)
  • Author(s): Nakasuka Fumie, Tabata Sho, Sakamoto Takeharu, Hirayama Akiyoshi, Ebi Hiromichi, Yamada Tadaaki, Umetsu Ko, Ohishi Maki, Ueno Ayano, Goto Hisatsugu, Sugimoto Masahiro, Nishioka Yasuhiko, Yamada Yasuhiro, Tomita Masaru, Sasaki Atsuo T, Yano Seiji, Soga Tomoyoshi
  • Journal Title: Communications Biology Volume: 4 Issue: 1 Pages: 1-12
  • DOI: 10.1038/s42003-021-02323-7
  • NAID: 120007178465
  • Peer Reviewed / Open Access
• [Journal Article] Circulating tumor DNA-guided treatment with pertuzumab plus trastuzumab for HER2-amplified metastatic colorectal cancer: a phase 2 trial (2021)
  • Author(s): Nakamura Y、Okamoto W、Kato T、Esaki T、Kato K、Komatsu Y、Yuki S、Masuishi T、Nishina T、Ebi H、Sawada K、Taniguchi H、Fuse N、Nomura S、Fukui M、Matsuda S、Sakamoto Y、Uchigata H、Kitajima K、Kuramoto N、Asakawa T、Olsen S、Odegaard J、Sato A、Fujii S、Ohtsu A、Yoshino T
  • Journal Title: Nature Medicine Volume: 27 Issue: 11 Pages: 1899-1903
  • DOI: 10.1038/s41591-021-01553-w
  • Peer Reviewed
• [Journal Article] Unmasking BCL-2 Addiction in Synovial Sarcoma by Overcoming Low NOXA (2021)
  • Author(s): Fairchild Carter K.、Floros Konstantinos V.、Jacob Sheeba、Coon Colin M.、Puchalapalli Madhavi、Hu Bin、Harada Hisashi、Dozmorov Mikhail G.、Koblinski Jennifer E.、Smith Steven C.、Domson Gregory、Leverson Joel D.、Souers Andrew J.、Takebe Naoko、Ebi Hiromichi、Faber Anthony C.、Boikos Sosipatros A.
  • Journal Title: Cancers Volume: 13 Issue: 10 Pages: 2310-2310
  • DOI: 10.3390/cancers13102310
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] MAPKシグナル経路を標的とする分子標的治療 (2021)
  • Author(s): 衣斐寛倫
  • Journal Title: がん分子標的治療 (Journal of Molecular Targeted Therapy for Cancer) Volume: 18 Pages: 193-198
• [Journal Article] BIG BANG study (EPOC1703): multicentre, proof-of-concept, phase II study evaluating the efficacy and safety of combination therapy with binimetinib, encorafenib and cetuximab in patients with BRAF non-V600E mutated metastatic colorectal cancer (2020)
  • Author(s): Kotani D, Bando H, Taniguchi H, Masuishi T, Komatsu Y, Yamaguchi K, Nakajima T, Satoh T, Nishina T, Esaki T, Nomura S, Takahashi K, Iida S, Matsuda S, Motonaga S, Fuse N, Sato A, Fujii S, Ohtsu A, Ebi H, Yoshino T.
  • Journal Title: ESMO open Volume: 1 Issue: 1 Pages: e000624-e000624
  • DOI: 10.1136/esmoopen-2019-000624
  • Peer Reviewed / Open Access
• [Journal Article] Epithelial-to-Mesenchymal Transition is a Cause of Both Intrinsic and Acquired Resistance to KRAS G12C Inhibitor in KRAS G12C-Mutant Non-Small Cell Lung Cancer (2020)
  • Author(s): Adachi Y, Ito K, Hayashi Y, Kimura R, Tan TZ, Yamaguchi R, Ebi H.
  • Journal Title: Clinical Cancer Research Volume: 26 Issue: 22 Pages: 5962-5973
  • DOI: 10.1158/1078-0432.ccr-20-2077
  • Peer Reviewed
• [Journal Article] Japanese Society of Medical Oncology Clinical Guidelines: Molecular Testing for Colorectal Cancer Treatment, 4th edition (2020)
  • Author(s): Ebi H, Bando H, Taniguchi H, Sunakawa Y, Okugawa Y, Hatanaka Y, Hosoda W, Kumamoto K, Nakatani K, Yamazaki K.
  • Journal Title: Cancer Science Volume: 111 Issue: 10 Pages: 3962-3969
  • DOI: 10.1111/cas.14567
  • Peer Reviewed
• [Presentation] KRAS 変異癌における標的治療耐性機構の克服 (2022)
  • Author(s): 足立 雄太、新津 宏明 、衣斐 寛倫
  • Organizer: 第81回日本癌学会学術総会
  • Invited
• [Presentation] Relationship between circulating tumor DNA and molecular phenotype in colorectal cancer (2022)
  • Author(s): 衣斐寛倫
  • Organizer: 第81回日本癌学会学術総会
  • Invited
• [Presentation] Mechanisms of resistance to RAS-targeting therapies (2021)
  • Author(s): Hiromichi Ebi
  • Organizer: 第19回日本臨床腫瘍学会学術集会
  • Invited
• [Presentation] Perspectives for targeted therapy to colon cancer (2021)
  • Author(s): Hiromichi Ebi
  • Organizer: 第80回日本癌学会学術総会
  • Invited
• [Presentation] RAS 変異がんに対する分子標的治療 (2020)
  • Author(s): 衣斐寛倫
  • Organizer: 日本癌学会学術総会
  • Invited