| Project/Area Number |
16H06259
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| Research Category |
Grant-in-Aid for Young Scientists (A)
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| Allocation Type | Single-year Grants |
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| Research Field |
Digestive surgery
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| Research Institution | Japanese Foundation for Cancer Research |
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Principal Investigator |
Imamura Yu 公益財団法人がん研究会, 有明病院 消化器外科, 副医長 (70583045)
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| Research Collaborator |
Bass Adam J. Dana-Faber Cancer Insitute
Haraguchi Ikumi 公益財団法人がん研究会・がん研究所, がんゲノム研究部
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥24,050,000 (Direct Cost: ¥18,500,000、Indirect Cost: ¥5,550,000)
Fiscal Year 2018: ¥7,150,000 (Direct Cost: ¥5,500,000、Indirect Cost: ¥1,650,000)
Fiscal Year 2017: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000)
Fiscal Year 2016: ¥8,580,000 (Direct Cost: ¥6,600,000、Indirect Cost: ¥1,980,000)
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| Keywords | KRAS / 遺伝子増幅 / 食道胃接合部腺癌 / 胃癌 / 食道腺癌 / 食道癌 / 予後 / 分子標的治療 / MEK阻害剤 / copy number variant / 悪性度 |
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| Outline of Final Research Achievements |
KRAS amplifications occur most commonly in esophageal, gastric and ovarian adenocarcinomas. KRAS-amplified gastric cancer models show marked overexpression of the KRAS protein and are insensitive to MAPK blockade owing to their capacity to adaptively respond by rapidly increasing KRAS-GTP levels. Here we demonstrate that inhibition of the guanine-exchange factors SOS1 and SOS2 or the protein tyrosine phosphatase SHP2 can attenuate this adaptive process and that targeting these factors, both genetically and pharmacologically, can enhance the sensitivity of KRAS-amplified models to MEK inhibition in both in vitro and in vivo settings. These data demonstrate the relevance of copy-number amplification as a mechanism of KRAS activation, and uncover the therapeutic potential for targeting of these tumors through combined SHP2 and MEK inhibition.
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| Academic Significance and Societal Importance of the Research Achievements |
これまでKRAS遺伝子増幅は上部消化器腺癌や卵巣癌で頻度が高いが、その意義は不明である。我々は今回野生型KRAS遺伝子増幅に注目した。このKRAS遺伝子増幅を来した細胞ではKRASタンパクの過剰発現を来たし、MEK阻害剤に抵抗性を示すことが判明した。グアニン交換因子であるSOS1, SOS2, SHP2阻害することでこの抵抗性の状態から脱することを明らかにした。KRAS遺伝子増幅を来す腫瘍においてはMEK阻害剤とSHP2阻害剤の併用が期待できる。KRAS遺伝子に関して変異だけでなく野生株遺伝子増幅の腫瘍悪性化メカニズムを初めて明らかにすることができ、新たな治療体系の確立が可能となる。
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