功能基因组学揭示了胃癌治疗中药物协同作用的脱靶依赖性。

IF 6 1区 医学 Q1 GASTROENTEROLOGY & HEPATOLOGY
Gastric Cancer Pub Date : 2024-11-01 Epub Date: 2024-07-20 DOI:10.1007/s10120-024-01537-y
Ozen Leylek, Megan E Honeywell, Michael J Lee, Michael T Hemann, Gulnihal Ozcan
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引用次数: 0

摘要

背景:将分子靶向药物纳入联合化疗是提高癌症治疗效果的变革性方法。然而,要充分发挥这种方法的潜力,就必须清楚地了解药物协同作用背后的遗传依赖性。虽然传统化疗药物之间的相互作用已被充分研究,但分子靶向药物与传统化疗药物之间的相互作用仍是癌症治疗的前沿领域。因此,我们利用强大的功能基因组学方法来解码驱动胃腺癌分子靶向药物/化疗组合协同作用的基因组依赖关系,以满足胃癌治疗的关键需求:我们在胃腺癌细胞中筛选了 15 种分子靶向药剂/常规化疗药对之间的药理相互作用,并通过全基因组 CRISPR 筛选和基于 shRNA 的特征检测,研究了协同作用的基因组范围遗传依赖性。我们利用基于荧光和依赖裂解推断的细胞死亡动力学实验验证了细胞死亡的协同作用,并通过单基因敲除实验验证了遗传依赖性:结果:我们的联合筛选发现,SN-38/厄洛替尼是协同作用最强的药物组合。功能基因组学测定揭示了SN-38/厄洛替尼与SN-38相同的遗传依赖特征。值得注意的是,SN-38/厄洛替尼诱导的细胞死亡增强并改善了动力学,这归因于厄洛替尼抑制ABCG2的脱靶效应,而不是其对表皮生长因子受体的靶向效应:在强调主要药物靶点的精准医疗时代,我们的研究挑战了这一范式,展示了以脱靶依赖性为基础的强大协同作用。进一步剖析协同作用背后错综复杂的基因依赖关系,可以为开发更有效的胃癌联合治疗策略铺平道路。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy.

Functional genomics reveals an off-target dependency of drug synergy in gastric cancer therapy.

Background: Integrating molecular-targeted agents into combination chemotherapy is transformative for enhancing treatment outcomes in cancer. However, realizing the full potential of this approach requires a clear comprehension of the genetic dependencies underlying drug synergy. While the interactions between conventional chemotherapeutics are well-explored, the interplay of molecular-targeted agents with conventional chemotherapeutics remains a frontier in cancer treatment. Hence, we leveraged a powerful functional genomics approach to decode genomic dependencies that drive synergy in molecular-targeted agent/chemotherapeutic combinations in gastric adenocarcinoma, addressing a critical need in gastric cancer therapy.

Methods: We screened pharmacological interactions between fifteen molecular-targeted agent/conventional chemotherapeutic pairs in gastric adenocarcinoma cells, and examined the genome-scale genetic dependencies of synergy integrating genome-wide CRISPR screening with the shRNA-based signature assay. We validated the synergy in cell death using fluorescence-based and lysis-dependent inference of cell death kinetics assay, and validated the genetic dependencies by single-gene knockout experiments.

Results: Our combination screen identified SN-38/erlotinib as the drug pair with the strongest synergism. Functional genomics assays unveiled a genetic dependency signature of SN-38/erlotinib identical to SN-38. Remarkably, the enhanced cell death with improved kinetics induced by SN-38/erlotinib was attributed to erlotinib's off-target effect, inhibiting ABCG2, rather than its on-target effect on EGFR.

Conclusion: In the era of precision medicine, where emphasis on primary drug targets prevails, our research challenges this paradigm by showcasing a robust synergy underpinned by an off-target dependency. Further dissection of the intricate genetic dependencies that underlie synergy can pave the way to developing more effective combination strategies in gastric cancer therapy.

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来源期刊
Gastric Cancer
Gastric Cancer 医学-胃肠肝病学
CiteScore
14.70
自引率
2.70%
发文量
80
审稿时长
6-12 weeks
期刊介绍: Gastric Cancer is an esteemed global forum that focuses on various aspects of gastric cancer research, treatment, and biology worldwide. The journal promotes a diverse range of content, including original articles, case reports, short communications, and technical notes. It also welcomes Letters to the Editor discussing published articles or sharing viewpoints on gastric cancer topics. Review articles are predominantly sought after by the Editor, ensuring comprehensive coverage of the field. With a dedicated and knowledgeable editorial team, the journal is committed to providing exceptional support and ensuring high levels of author satisfaction. In fact, over 90% of published authors have expressed their intent to publish again in our esteemed journal.
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