関連する実験動画

Updated: Aug 6, 2025

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure

Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure

Published on: August 11, 2017

MEN1変異はメンイン抑制に対する臨床抵抗を媒介する

Florian Perner^1,2, Eytan M Stein³, Daniela V Wenge¹

¹Department of Pediatric Oncology, Dana-Farber Cancer Institute, Division of Hematology/Oncology, Boston Children's Hospital and Harvard Medical School, Boston, MA, USA.

|March 16, 2023

まとめ

メニン阻害剤は特定の白血病の治療に有望である. しかし,MEN1遺伝子の変異によって得られた耐性が生じ,メニンとMLL1をクロマチンに保持することで癌細胞が治療を回避できる.

科学分野:

血液学
分子生物学
癌研究

背景:

染色体結合タンパク質は,特に血液形成において,細胞状態を調節する.
KMT2Aの再編成またはNPM1変異を含む白血病は,白血病原性遺伝子発現のためのメニンタンパク質に依存しています.
レヴュメニブのようなメニン阻害剤は,メニン- MLL1相互作用を阻害することで,これらの白血病の臨床有効性を示しています.

研究の目的:

KMT2ArおよびNPM1変異性白血病におけるメニン阻害剤に対する耐性のメカニズムを調査する.
標的治療に対する耐性を引き起こす遺伝的変異を特定する.
耐性変異が薬標的相互作用とクロマチンの占有率にどのように影響するかを理解する.

主な方法:

リヴュメニブに耐性を持つ患者のMEN1遺伝子の体内変異の分析
異種移植モデルにおける抵抗機構の検証
抵抗変異を特定するために偏りのないベースエディター画面を使用します.
変異したメンニブタンパク質の生化学的および構造的分析と,レヴメニブおよびMLL1との相互作用.

主要な成果:

MEN1の体内変異は,レブメニブ-メニンのインターフェイスで,耐性患者のサンプルで特定されました.
これらの変異は,臨床前モデルで保存され,偏見のないスクリーニングで特定されました.
変異はレヴュメニブ結合を減少させる構造的変化を引き起こすが,メニン- MLL1の相互作用を維持する.
薬剤によるメニンとMLL1の脱出を阻害する.

結論:

メニン阻害剤に対する獲得抵抗は,薬物結合界面の特定のMEN1変異によって引き起こされる.
これらの変異は,KMT2ArおよびNPM1変異性白血病における保存された抵抗メカニズムを表しています.
この研究では,治療的選択圧が抵抗性変異を誘導し,クロマチンを標的とする薬剤における潜在的な一般的な抵抗性メカニズムである,持続的なクロマチンの占有率につながることを示しています.

さらに関連する動画

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms

Published on: December 9, 2015

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

関連する概念動画

mTOR Signaling and Cancer Progression

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...

Treatment Resistant Cancers

Treatment Resistant Cancers

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...

Abnormal Proliferation

Abnormal Proliferation

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...

Mitogens and the Cell Cycle

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...

Mismatch Repair

Mismatch Repair

Organisms are capable of detecting and fixing nucleotide mismatches that occur during DNA replication. This sophisticated process requires identifying the new strand and replacing the erroneous bases with correct nucleotides. Mismatch repair is coordinated by many proteins in both prokaryotes and eukaryotes.
The Mutator Protein Family Plays a Key Role in DNA Mismatch Repair
The human genome has more than 3 billion base pairs of DNA per cell. Prior to cell division, that vast amount of genetic...

Inhibition of Cdk Activity

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...