mTORC2促进胰腺癌的进展和对parp抑制剂的抵抗
Chiwen Bu1,2, Ligang Zhao1, Lishan Wang1
1Department of Hepatobiliary and Pancreatic Surgery, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, 210009, China.
Oncology research
|July 7, 2023
概括
向mTORC2可以提高胰腺癌中PARP抑制剂的有效性. 这项研究揭示了mTORC2促进癌症生长和耐药性,为治疗野生型BRCA1/2突变患者提供了一种新策略.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 癌症治疗方法 癌症治疗方法
背景情况:
- 胰腺癌的预后不好,除了传统化疗之外,治疗选择有限.
- 聚 ((ADP-ribose) 聚合酶 (PARP) 抑制剂为BRCA1/2-突变胰腺癌提供向治疗,但大多数患者患有野生型BRCA1/2并且具有抗性.
- 猛素复合体2 (mTORC2) 的哺乳动物点与癌症进展有关.
研究的目的:
- 研究mTORC2在胰腺癌生长中的作用及其作为治疗点的潜力.
- 为了确定mTORC2的向是否可以克服胰腺癌中对PARP抑制剂的耐药性.
- 阐明mTORC2影响DNA修复途径的机制.
主要方法:
- 在胰腺癌组织中分析了mTORC2的过度表达.
- 进行了mTORC2子单元Rictor的 Knockdown,以评估对olaparib的敏感性.
- 研究了同源重组 (HR) 修复机制,包括BRCA1对DNA双链断裂 (DSB) 的招募.
- 与mTORC2抑制剂 (PP242) 和olaparib联合治疗在体内进行了评估.
主要成果:
- mTORC2在胰腺癌中过度表达,促进细胞生长和入侵.
- 里克托 knockdown使胰腺癌细胞对PARP抑制剂olaparib敏感.
- mTORC2通过影响BRCA1招募到DSBs来积极调节HR修复.
- 使用PP242和olaparib的联合治疗在体内协同抑制了瘤生长.
结论:
- mTORC2是胰腺癌同源重组修复的关键调节者.
- 向mTORC2是一种新的策略,可以提高PARP抑制剂在胰腺癌中的疗效,特别是在野生型BRCA1/2.2患者中.
- 这项研究为更广泛的胰腺癌患者提供了有希望的治疗方法.
相关概念视频
03:03mTOR Signaling and Cancer Progression
3.8K
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...
The mTOR pathway or the...
3.8K
01:22PI3K/mTOR/AKT Signaling Pathway
3.7K
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a...
3.7K
02:23Abnormal Proliferation
4.6K
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...
4.6K
01:05Cancer-Critical Genes II: Tumor Suppressor Genes
7.5K
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...
7.5K
02:07Tumor Progression
6.4K
Tumor progression is a phenomenon where the pre-formed tumor acquires successive mutations to become clinically more aggressive and malignant. In the 1950s, Foulds first described the stepwise progression of cancer cells through successive stages.
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...
Colon cancer is one of the best-documented examples of tumor progression. Early mutation in the APC gene in colon cells causes a small growth on the colon wall called a polyp. With time, this polyp grows into a benign, pre-cancerous tumor. Further...
6.4K
02:56Treatment Resistant Cancers
3.3K
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...
3.3K