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.
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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。
DOI：
10.1101/2023.10.07.561351
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Ozcan,Gulnihal
中科院分区：
文献类型：
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作者：
Leylek,Ozen;Honeywell,MeganE;Lee,MichaelJ;Hemann,MichaelT;Ozcan,Gulnihal
背景将分子靶向药物整合到联合化疗中对于提高癌症的治疗效果具有变革性意义。然而，实现这种方法的全部潜力需要清楚地理解药物协同作用的遗传依赖性。虽然常规化疗药物之间的相互作用已得到充分研究，但分子靶向药物与常规化疗药物的相互作用仍然是癌症治疗的前沿。因此，我们利用一个强大的功能基因组学方法来解码基因组依赖性，驱动协同作用的分子靶向药物/化疗组合在胃腺癌，解决了胃癌therapy.MethodsWe筛选药理学之间的相互作用十五分子靶向药物/常规化疗对胃腺癌细胞，并检查了整合全基因组CRISPR筛选与基于shRNA的签名测定的协同作用的基因组规模遗传依赖性。我们验证了协同作用，在细胞死亡中使用基于荧光和裂解依赖的推断细胞死亡动力学测定，并验证了遗传依赖性通过单基因敲除experiments.ResultsOur组合筛选确定SN-38/厄洛替尼作为药物对最强的协同作用。功能基因组学测定揭示了SN-38/厄洛替尼与SN-38相同的遗传依赖性特征。值得注意的是，SN-38/厄洛替尼诱导的增强的细胞死亡与改善的动力学归因于厄洛替尼的脱靶效应，抑制ABCG 2，而不是其对EGFR.ConclusionIn精确医学的时代，强调主要药物靶点盛行，我们的研究挑战这种模式，展示了强大的协同作用支持的脱靶依赖性。进一步剖析协同作用背后复杂的遗传依赖性，可以为开发更有效的胃癌治疗联合策略铺平道路。
BackgroundIntegrating 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.MethodsWe 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.ResultsOur 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.ConclusionIn 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.