静かな変異は,RAS Q61がんにおける治療的脆弱性を明らかにする
Yoshihisa Kobayashi1,2,3, Chhayheng Chhoeu4, Jiaqi Li5
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. yoshikob@ncc.go.jp.
Nature
|March 3, 2022
まとめ
研究者らは,静かなKRAS変異 (G60G) が,がんにおける機能的なKRAS (Q61K) 腫瘍遺伝子の生成に不可欠であることを発見した. この発見は,RAS ((Q61)) がんを標的とした新しい治療戦略を明らかにし,スプライシングを妨害する.
科学分野:
- 腫瘍学
- 分子生物学
- 遺伝学
背景:
- RASファミリーのタンパク質はヒトがんにおける重要な腫瘍遺伝子であり,KRAS (G12C) 阻害剤は臨床的有効性を示しています.
- 既存の治療法では,G12C以外のNRAS,HRAS,またはKRASの変種をターゲットにせず,重要な満たされていないニーズを残しています.
- RASタンパク質の機能的状態は,代替スプライシングのような転写後の改変と密接に関連しています.
研究 の 目的:
- 機能的なKRAS (Q61K) 変種が生成されるメカニズムを解明する.
- RAS (Q61) 変異によって引き起こされるがんの新たな治療標的を特定する.
- 腫瘍遺伝子の活性化と潜在的な治療介入における 静かな変異の役割を調査する.
主な方法:
- 分子生物学技術を用いて,KRAS (Q61K) タンパク質生成における静かなKRAS G60G変異の役割を調査した.
- KRAS変異に関連した代替スプライシングイベントと早期のタンパク質終了を分析した.
- エキゾニック・スプライシング・エンハンサー (ESE) モチーフを標的とした,変異特有の反意味オリゴヌクレオチドを設計し,テストした.
主要な成果:
- クリプティックスプライスサイト形成と代替スプライシングを防ぐため,機能的なKRAS ((Q61K) の生成には静かなKRAS G60G変異が必要です.
- KRAS ((Q61K) とG60G/ A59Aの静かな変異は,三つの独立したパンガンコホートで一致していることが判明しました.
- ESEモチーフを標的としたアンチセンスオリゴヌクレオチドは,選択的にRAS (Q61) 機能を阻害し,in vitroおよびin vivoで治療効果を示した.
結論:
- この研究は,RAS (Q61K) 腫瘍遺伝子の活性化のための新しいスプライシング依存メカニズムを発見した.
- この研究は,異常なスプライシングをターゲットにすることで,RAS ((Q61) がんの変異選択的治療戦略を特定しています.
- この発見は,スプライシングの脆弱性を利用することで,他の遺伝子に起因する癌の治療に有望なアプローチになる可能性があることを示唆しています.
関連する概念動画
The Ras Gene
6.5K
The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a...
Ras is a...
6.5K
Abnormal Proliferation
4.7K
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.7K
Small GTPases - Ras and Rho
4.3K
Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
Three regulatory proteins control their activity:
4.3K
Cancer-Critical Genes II: Tumor Suppressor Genes
8.3K
Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...
8.3K
The Retinoblastoma Gene
4.2K
Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
The first-ever tumor suppressor gene called Rb was identified in retinoblastoma - a rare eye tumor in children. In inherited forms of the disease, a child inherits one defective copy of the Rb gene, which predisposes them to retinoblastoma. However,...
4.2K
Loss of Tumor Suppressor Gene Functions
5.2K
Tumor suppressor genes are normal genes that can slow down cell division, repair DNA mistakes, or program the cells for apoptosis in case of irreparable damage. Hence, they play an essential role in preventing the proliferation of damaged cells.
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
When the tumor suppressor genes develop mutations or are lost, cells start growing out of control, leading to cancer. However, a single functional copy of the tumor suppressor gene is enough for the cells to maintain their normal functions and cell...
5.2K


