ARAF変異は,メラノーマにおけるRAF阻害剤ベルバラフェニブに抵抗性を与える

Ivana Yen¹, Frances Shanahan¹, Jeeyun Lee^2,3

¹Department of Discovery Oncology, Genentech Inc., South San Francisco, CA, USA.

Nature

|May 6, 2021

まとめ

ベルヴァラフェニブはRAFジマー阻害剤であり,メラノーマでは有望ですが,耐性が発達する可能性があります. RAFとMEK阻害剤のような組み合わせ療法で克服できると示唆しています.

科学分野:

腫瘍学
分子生物学
薬理学について

背景:

RAF単体阻害剤 (I. 5型) は,BRAF^V600変異のメラノーマに対して承認されているが,他の変異に対して無効である.
ベルヴァラフェニブは,BRAF^V600EおよびNRAS変異性メラノーマにおける臨床的活性を持つII型RAFダイマー阻害剤である.

研究の目的:

BRAF^V600EまたはRAS変異の進行した固体腫瘍におけるベルヴァラフェニブの安全性,耐受性,および初期有効性を調査する.
NRAS変異性メラノーマにおけるベルバラフェニブに対する耐性のメカニズムを特定する.

主な方法:

ベルヴァラフェニブの第I相臨床試験 (NCT02405065,NCT03118817)
ベルヴァラフェニブ耐性NRAS変異性メラノーマ細胞の生成
ベルヴァラフェニブで治療された患者の循環中の腫瘍DNAの分析

主要な成果:

ARAFキナーゼドメインの新たな再発性突然変異がベルヴァラフェニブに対する耐性を引き起こすと特定された.
ベルヴァラフェニブがARAF変異型ジマーを誘発すると,ARAF変異はジマーとキナーゼ活動に依存して抵抗性をもたらした.
ARAF変異体は他のII型RAF阻害剤に対する感受性の低下を示し,一般的な耐性メカニズムを示唆した.

結論:

ARAF変異は,メラノーマにおけるRAFダイマー阻害剤に対する有意な耐性メカニズムを表しています.
RAFおよびMEK阻害剤を併用した治療は,ARAFによる耐性を克服することができる.
RAFダイマーを標的とし,レジスタンス経路を理解することは,効果的なメラノーマ治療に不可欠です.

さらに関連する動画

06:44

Author Spotlight: Integrating BRET-Based Assays and Rare Mutation Analysis to Decipher RAF Kinase Regulation in Live Cells

Published on: March 1, 2024

1.4K

06:09

Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells

Published on: June 7, 2019

9.1K

関連する概念動画

01:07

MAPK Signaling Cascades

6.9K

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...

6.9K

02:50

Combination Therapies and Personalized Medicine

5.4K

Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...

5.4K

02:38

The Ras Gene

6.6K

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...

6.6K

01:20

The Retinoblastoma Gene

4.3K

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,...

4.3K

02:57

Targeted Cancer Therapies

8.0K

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...

8.0K

03:03

mTOR Signaling and Cancer Progression

4.0K

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...