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

2019 Fiscal Year Final Research Report

• 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
• Keywords: KRAS / 上皮間葉移行 / シグナル伝達

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.

Free Research Field

腫瘍内科学

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。