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首页> 外文期刊>Journal of Molecular Biology >Exploiting Synthetic Lethality and Network Biology to Overcome EGFR Inhibitor Resistance in Lung Cancer
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Exploiting Synthetic Lethality and Network Biology to Overcome EGFR Inhibitor Resistance in Lung Cancer

机译：利用综合性致死性和网络生物学来克服肺癌EGFR抑制剂抗性

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Abstract Despite the recent approval of third-generation therapies, overcoming resistance to epidermal growth factor receptor (EGFR) inhibitors remains a major challenge in non-small cell lung cancer. Conceptually, synthetic lethality holds the promise of identifying non-intuitive targets for tackling both acquired and intrinsic resistance in this setting. However, translating these laboratory findings into effective clinical strategies continues to be elusive. Here, we provide an overview of the synthetic lethal approaches that have been employed to study EGFR inhibitor resistance and review the oncogene and non-oncogene signalling mechanisms that have thus far been unveiled by synthetic lethality screens. We highlight the potential challenges associated with progressing these discoveries into the clinic including context dependency, signalling plasticity, and tumour heterogeneity, and we offer a perspective on emerging network biology and computational solutions to exploit these phenomena for cancer therapy and biomarker discovery. We conclude by presenting a number of tangible steps to bolster our understanding of fundamental synthetic lethality mechanisms and advance these findings beyond the confines of the laboratory. Graphical Abstract Display Omitted Highlights ? Resistance to EGFR inhibitors in mutant EGFR lung cancer is a major clinical problem. ? Synthetic lethal screens have been used to identify targets to overcome resistance. ? Translating synthetic lethal hits into novel therapies remains challenging. ? Exploiting network biology and tumour heterogeneity may represent potential solutions.
机译：摘要尽管最近批准了第三代疗法，但克服表皮生长因子受体（EGFR）抑制剂的耐受性仍然是非小细胞肺癌的主要挑战。概念上，合成的致命性具有识别在该环境中识别不良目标的非直观目标的承诺。然而，将这些实验室发现转化为有效的临床策略继续难以难以捉摸。在这里，我们概述了已经用于研究EGFR抑制剂抗性的合成致死方法，并审查迄今为止通过合成致死筛网揭开的癌基因和非癌基因信号传导机制。我们突出了与将这些发现进入诊所的潜在挑战，包括上下文依赖性，信号塑性和肿瘤异质性，并且我们提供了新兴网络生物学和计算解决方案的视角，以利用这些现象癌症治疗和生物标志物发现。我们通过介绍一些有形步骤来加强我们对基本合成致命机制的理解，并推进超出实验室范围的这些发现。图形抽象显示省略了亮点？突变EGFR肺癌中EGFR抑制剂的抗性是一个主要的临床问题。还是合成致命筛网已被用于识别克服抗性的目标。还是将合成的致命击中转化为新的疗法仍然具有挑战性。还是利用网络生物学和肿瘤异质性可以代表潜在的解决方案。

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