2022 Fiscal Year Final Research Report
Internalization mechanism of anti-EGFR antibody drugs in RAS wild-type colorectal cancer cell lines
| Project/Area Number |
20K16305
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 50010:Tumor biology-related
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| Research Institution | The University of Tokushima |
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Principal Investigator |
FUKUYA Akira 徳島大学, 大学院医歯薬学研究部(医学域), 徳島大学専門研究員 (30780051)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | colon cancer / EGFR / Cetuximab / Panitumumab / internalization / early tumor shrinkage / lysosome / depth of response |
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| Outline of Final Research Achievements |
We quantified the amount of EGFR on the plasma membrane by fluorescence microscopy in colorectal cancer cell lines, and identified clathrin-dependent internalization of anti-EGFR antibody drugs by siRNA and specific inhibitors. Proteome analysis of the protein extracted from anti-EGFR antibody-treated cells identified UBR4 as a gene associated with intracellular dynamics, and UBR4 was predominantly co-localized with EGFR by fluorescence double immunization upon addition of anti-EGFR antibody-treated cells. Knockdown of UBR4 suppressed the effects of anti-EGFR antibody drugs on cell proliferation and apoptosis, and also suppressed degradation of Lysosomes. Intratumor expression of UBR4 in clinical specimens correlated with anti-tumor efficacy and overall survival.
Translated with www.DeepL.com/Translator (free version)
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| Free Research Field |
消化器
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| Academic Significance and Societal Importance of the Research Achievements |
本研究で得た効果予測バイオマーカーUBR4は実臨床において従来治療よりも抗EGFR抗体薬に奏功する患者群の選定に寄与できる可能性がある。また腫瘍内発現を免疫染色により簡便に得られることより生検検体のみで治療効果予測できることは非常に意義が大きい。さらに抗EGFR抗体薬は大腸癌以外に頭頸部癌、肺がんなどに保険適応されており、本研究成果が今後他の癌種にも応用できる可能性が秘められていると考える。最終的には抗EGFR抗体薬と結合したEGFRの細胞内動態の解明が大腸癌の個別化医療に寄与し大腸癌患者のQOLを保ち、より長期にわたる生存期間を得ることが可能になると思われる。
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