封面專題•COVER STORY 澳大新語•2020 UMAGAZINE 22 25 ARID1A是一種抑癌基因。沈教授表 示，基因突變是結腸直腸癌的成因之 一，包括致癌基因突變和抑癌基因突 變。對付致癌基因突變的方法，主要是 靶向抑制致癌基因生長，但醫護人員遇 上抑癌基因突變時，卻難以採取靶向治 療，是臨床上一大挑戰。 合成致死是指兩個或以上的搭檔基因同 時被抑制導致細胞死亡的現象。由於癌 細胞至少有一種基因（抑癌基因）存在 缺陷，因此用合成致死的方法對付抑 癌基因突變，可以精準命中癌細胞。沈 教授說：「我們通過高通量篩選，發現 ARID1A基因的合成致死搭檔為Aurora Kinase A蛋白。當ARID1A基因突變， 只要抑制Aurora Kinase A蛋白的活動， 就能精準殺死癌細胞。」 沈教授團隊的研究在動物測試上取得良好 效果，下一步將會研究合成致死的概念如 何應用於結腸直腸癌的其它抑癌基因， 以及其他癌症的抑癌基因。他們還將致力 研發新型Aurora Kinase A抑制劑，治療 ARID1A突變引起的結腸直腸癌。 ARID1A is a tumour suppressor gene. According to Prof Shim, one of the causes of colorectal cancer is genetic mutations, including oncogene mutations and tumour suppressor mutations. Current targeted cancer therapies focus primarily on inhibiting tumour oncogene. However, it has been a major clinical challenge to deal with tumour suppressor mutations, as they cannot be targeted by drugs. Synthetic lethality is a genetic interaction between two (or more) genes where a single gene deficiency is tolerable for cell viability, whereas deficiencies in both genes lead to cell death. As cancer cells have existing deficiencies in at least one gene (tumour suppressor), the synthetic lethality approach for the mutant tumour suppressor enables medical personnel to target cancer cells precisely. Prof Shim says: ‘By using high throughput screening approach, we identified Aurora Kinase A as the synthetic lethal partner of ARID1A. When the ARID1A gene mutates, as long as the activity of the Aurora Kinase A is inhibited, the cancer cells can be killed precisely.’ Prof Shim's team has achieved good research results in animal testing. The team’s next step is to expand the application of the synthetic lethality concept to other tumour suppressor genes in colorectal and other types of cancer. Prof Shim’s team is also committed to developing new Aurora Kinase A inhibitors to treat colorectal cancer cells carrying ARID1A mutations. 沈仲燮教授研究多種抑癌基因，包括p53、PTEN、RB1、BRCA1、ARID1A及SMAD4，致力找出它們的合成 致死搭檔。加入澳大前，曾於美國約翰．霍普金斯大學醫學院擔任副研究員。目前是期刊《Molecular Medicine Reports》的編輯委員會成員。 Prof Shim Joong Sup is currently studying a variety of tumour suppressor genes, including p53, PTEN, RB1, BRCA1, ARID1A, and SMAD4. He is committed to identifying their synthetic lethal partners. Before joining UM, he was a research associate at John Hopkins University School of Medicine in the United States. He is currently a member of the editorial board of the journal Molecular Medicine Reports. 運用遺傳學理論——「合成致死」治療結腸直腸癌 Applying the genetic theory of ‘synthetic lethality’ in the treatment of colorectal cancer
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