在晚期前列腺癌中,IGFBP3通过调节EGFR信号来促进对Olaparib的耐药性
Amy R Leslie1, Shu Ning1, Cameron M Armstrong1
1Department of Urologic Surgery, University of California Davis, Davis, CA, USA.
iScience
|February 8, 2024
概括
胰岛素样生长因子结合蛋白3 (IGFBP3) 通过增强DNA修复,驱动前列腺癌中对Olaparib的耐药性. 抑制IGFBP3或EGFR恢复了Olaparib的敏感性,提供了新的治疗策略.
科学领域:
- 在瘤学瘤学.
- 分子生物学分子生物学
- 癌症研究 癌症研究
背景情况:
- 奥拉巴里布是一种PARP抑制剂 (PARPi),用于治疗具有DNA修复缺陷的前列腺癌.
- 对olaparib的临床耐药性是割耐性前列腺癌 (CRPC) 的一个重大挑战.
研究的目的:
- 研究前列腺癌中获得的Olaparib耐药性的机制.
- 为了确定潜在的治疗点来克服Olaparib耐药性.
主要方法:
- 开发了对Olaparib耐药 (OlapR) 的前列腺癌细胞系 (LNCaP,C4-2B).
- 在耐药模型中评估胰岛素类生长因子结合蛋白3 (IGFBP3) 表达.
- 研究了IGFBP3,EGFR和DNA-PKcs在DNA修复和Olaparib耐药性的作用.
- 利用基因沉默和EGFR抑制 (Gefitinib) 来评估治疗策略.
主要成果:
- 在获得的和内在的Olaparib耐药前列腺癌模型中观察到高IGFBP3表达.
- 通过通过EGFR和DNA-PKcs激活增强DNA修复,IGFBP3促进了Olaparib的耐药性.
- 通过增加DNA损伤和细胞死亡,IGFBP3的枯竭使得耐药细胞对Olaparib重新敏感.
- EGFR抑制模仿IGFBP3抑制,降低细胞活力并恢复olaparib的敏感性.
结论:
- IGFBP3是前列腺癌中Olaparib耐药性的关键调解者.
- 向IGFBP3或EGFR是一个有希望的策略,可以克服对Olaparib的获得性耐药性.
- 联合抑制PARP和EGFR/IGFBP3通路可能会提高治疗疗效.
相关概念视频
02:38Mitogens and the Cell Cycle
6.5K
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...
6.5K
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
01:19Interactions Between Signaling Pathways
6.3K
Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.3K
01:22PI3K/mTOR/AKT Signaling Pathway
3.6K
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...
3.6K
02:23Abnormal Proliferation
4.5K
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...
4.5K
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