Development of treatment strategy against KRAS mutant cancer by targeting PI3K and ERK

• Project/Area Number: 26830105
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Tumor therapeutics
• Research Institution: Kanazawa University
• Principal Investigator: Hiromichi Ebi 金沢大学, がん進展制御研究所, 准教授 (00645145)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: がん / KRAS / MEK阻害剤 / フィードバック / 癌 / 上皮間葉移行 / MEK阻害薬 / PI3キナーゼ / ERKシグナル

Outline of Final Research Achievements

KRAS is frequently mutated in a variety of cancers including lung cancer. Whereas the mitogen-activated protein kinase (MAPK) is a well-known effector pathway of KRAS, blocking this pathway with clinically-available MAPK inhibitors is relatively ineffective. Treatment with MEK inhibitors in KRAS mutant lung cancers lead to feedback activation of the MAPK pathway. In epithelial-like KRAS mutant lung cancers, this feedback was attributed to ERBB3-mediated re-activation of MEK. In contrast, in mesenchymal-like KRAS mutant lung cancers, the feedback was contributed to the fibroblast growth factor receptor 1 (FGFR1) pathway. Combination of MEK inhibitor trametinib with an FGFR inhibitor induced cell death in vitro in mesenchymal-like KRAS mutant cancers. These observations indicate that feedback activation of FGFR1 signaling mitigates the effect of MEK inhibitor in mesenchymal-like KRAS mutant lung tumors, and could establish a therapeutic approach to treat these cancers.

Research Products

• [Int'l Joint Research] Virginia Commonwealth University(米国)
• [Journal Article] High efficacy of third generation EGFR inhibitor AZD9291 in a leptomeningeal carcinomatosis model with EGFR-mutant lung cancer cells (2016)
  • Author(s): Nanjo S, Ebi H, Arai S, Takeuchi S, Yamada T, Mochizuki S, Okada Y, Nakada M, Murakami T, Yano S.
  • Journal Title: Oncotarget Volume: 7(4) Issue: 4 Pages: 3847-3856
  • DOI: 10.18632/oncotarget.6758
  • NAID: 120005830568
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Co-active receptor tyrosine kinases mitigate the effect of FGFR inhibitors in FGFR1-amplified lung cancers with low FGFR1 protein expression (2015)
  • Author(s): Hiromichi Ebi, Hiroshi Kotani, Hidenori Kitai, Shigeki Nanjo, Kenji Kita, Seiji Yano, Akishi Ooi, Tiffany Huynh, Mari Mino-Kenudson, and Anthony C. Faber
  • Journal Title: Oncogene Volume: 未定 Issue: 27 Pages: 3587-97
  • DOI: 10.1038/onc.2015.426
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Measurement of PIP3 levels reveals an unexpected role for p110β in early adaptive responses to p110α-specific inhibitors in luminal breast cancer. (2015)
  • Author(s): Costa C, Ebi H, Martini M, Beausoleil SA, Faber AC, Jakubik CT, Huang A, Wang Y, Nishtala M, Hall B, Rikova K, Zhao J, Hirsch E, Benes CH, Engelman JA.
  • Journal Title: Cancer Cell Volume: 27 Issue: 1 Pages: 97-108
  • DOI: 10.1016/j.ccell.2014.11.007
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Lack of association between the BIM deletion polymorphism and the risk of lung cancer with and without EGFR mutations. (2015)
  • Author(s): Ebi H, Yano S, et al.
  • Journal Title: J Thorac Oncol Volume: 10 Issue: 1 Pages: 59-66
  • DOI: 10.1097/jto.0000000000000371
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Assessment of ABT-263 activity across a cancer cell line collection leads to a potent combination therapy for small-cell lung cancer. (2015)
  • Author(s): Faber AC, Ebi H, Engelman JA et al.
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 112 Issue: 11
  • DOI: 10.1073/pnas.1411848112
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Japanese Society of Medical Oncology Clinical Guidelines: RAS (KRAS/NRAS) mutation testing in colorectal cancer patients (2015)
  • Author(s): Taniguchi H, Yamazaki K, Yoshino T, Muro K, Yatabe Y, Watanabe T, Ebi H, Ochiai A, Baba E, Tsuchihara K.
  • Journal Title: Ｃａｎｃｅｒ Ｓｃｉｅｎｃｅ Volume: 106 Issue: 3 Pages: 324327-324327
  • DOI: 10.1111/cas.12595
  • Peer Reviewed / Open Access
• [Journal Article] Not just gRASping at flaws: finding vulnerabilities to develop novel therapies for treating KRAS mutant cancers. (2014)
  • Author(s): Ebi H, Yano S, et al.
  • Journal Title: Cancer Sci Volume: 105 Issue: 5 Pages: 499-505
  • DOI: 10.1111/cas.12383
  • NAID: 120005830600
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Combinatorial approach targeting KRAS mutant cancers (2015)
  • Author(s): Hiromichi Ebi
  • Organizer: The 20th JFCR－ISCC
  • Place of Presentation: Miraikan National Museum of Emerging Science and Innovation, Koto-ku, Tokyo
  • Year and Date: 2015-12-09
  • Int'l Joint Research / Invited
• [Presentation] Translational research for targeting BRAF and KRAS mutant cancers (2014)
  • Author(s): Ｈｉｒｏｍｉｃｈｉ Ｅｂｉ
  • Organizer: 日本臨床腫瘍学会
  • Place of Presentation: 福岡
  • Year and Date: 2014-07-17 – 2014-07-19
  • Invited
• [Book] 医学のあゆみ (2015)
  • Author(s): 衣斐寛倫
  • Total Pages: 5
  • Publisher: 医歯薬出版株式会社
• [Book] 日本胸部臨床 (2015)
  • Author(s): 衣斐寛倫
  • Total Pages: 10
  • Publisher: 克誠堂出版株式会社
• [Book] 実験医学増刊 (2015)
  • Author(s): 衣斐寛倫
  • Total Pages: 6
  • Publisher: 羊土社
• [Patent(Industrial Property Rights)] 特許権 (2015)
  • Inventor(s): 衣斐寛倫、矢野聖二、北井秀典
  • Industrial Property Rights Holder: 国立大学法人金沢大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2015-227015
  • Filing Date: 2015-11-19