结合分子动力学和机器学习,预测药物耐药性,在结肠直肠癌中引起BRAF变异
Longsheng Xie1, Christopher Lockhart1, Dmitri K Klimov1
1School of Systems Biology, George Mason University, Fairfax, VA 22020, USA.
Molecules (Basel, Switzerland)
|September 13, 2025
概括
BRAF突变驱动着结直肠癌的耐药性. 分子动力学和机器学习确定了影响对BRAF抑制剂 (如达布拉费尼布和韦穆拉费尼布) 耐药性的关键蛋白质残留物.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 计算化学计算化学
背景情况:
- BRAF蛋白突变,特别是V600E,在结直肠癌 (CRC) 中很普遍.
- 由于原发性和获得性耐药性,BRAF突变导致预后不佳,并带来治疗挑战.
- 了解BRAF结构变化对于克服治疗耐药性至关重要.
研究的目的:
- 研究与药物耐药性相关的BRAF突变中的结构变化.
- 为了确定参与BRAF抑制剂耐药性机制的关键残留物.
- 为BRAF突变驱动的耐药性表型开发预测模型.
主要方法:
- 复制品交换分子动力学模拟.
- 机器学习技术用于数据分析.
- 对BRAF蛋白质的形状变化的分析.
主要成果:
- 突变BRAF蛋白的特定构造变化与药物敏感性/耐药性相关.
- 确定了关键的残留物 (例如,达布拉费尼布的psi494,phi600;维穆拉费尼布的psi450,phi484).
- 这些残留物位于CR3的ATP结合N中,调节酶活性.
结论:
- 对BRAF突变的结构洞察力解释了耐药性机制.
- 预测模型可以指导针对耐药性CRC的个性化治疗策略.
- 针对特定的BRAF变体提供了改善CRC治疗结果的潜力.
更多相关视频
09:58Using RNA-sequencing to Detect Novel Splice Variants Related to Drug Resistance in In Vitro Cancer Models
Published on: December 9, 2016
14.3K
10:16Employing Digital Droplet PCR to Detect BRAF V600E Mutations in Formalin-fixed Paraffin-embedded Reference Standard Cell Lines
Published on: October 8, 2015
13.6K
相关概念视频
Treatment Resistant Cancers
3.7K
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...
3.7K
Adaptive Mechanisms in Cancer Cells
7.0K
Cancer cells accumulate genetic changes at an abnormally rapid rate due to the defects in the DNA repair mechanisms. From an evolutionary perspective, such genetic instability is advantageous for cancer development. Mutant cell lines accumulate a series of beneficial mutations that contribute to their progression into cancer.
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
7.0K
Combination Therapies and Personalized Medicine
5.9K
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...
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...
5.9K
