Evolution of Relapse-Proficient Subclones Constrained by Collateral Sensitivity to Oncogene Overdose in Wnt-Driven Mammary Cancer.
Evolution of Relapse-Proficient Subclones Constrained by Collateral Sensitivity to Oncogene Overdose in Wnt-Driven Mammary Cancer.
复制标题
Wnt 驱动的乳腺癌中对癌基因过量的附带敏感性限制了复发性亚克隆的进化。
DOI：
10.1016/j.celrep.2018.12.096
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发表时间：
2019
期刊：
影响因子：
8.8
通讯作者：
Gunther,EdwardJ
中科院分区：
文献类型：
--
作者：
Keller,RossR;Gunther,EdwardJ
靶向癌症治疗药物选择耐药救援亚克隆(RSCs)，这种亚克隆通常携带恢复致癌信号的救援突变。虽然抗生素耐药性背后的突变经常会给药物幼稚的微生物带来适应成本的负担，但目前尚不清楚在靶向治疗之前，癌症复发的补救突变是否以及如何遇到负面选择。在这里，使用可逆的Wnt驱动的乳腺癌小鼠模型，我们发现了在RSCs的克隆进化过程中对Wnt信号过量的严格反选择。通过多区域DNA测序分析模拟靶向治疗(Wnt撤除)过程中出现的复发肿瘤，发现由多个RSC组成的多克隆复发，这些RSC具有截然不同但功能相同的挽救突变，这些突变汇聚在次最大Wnt通路激活上。当叠加在天然(即未加药)信号上时，这些挽救突变面临负选择，这表明它们在Wnt退出之前给RSC带来了适应成本，从而揭示了它们的选择优势。利用癌基因过量的侧支敏感性可能有助于消除RSCs，防止癌症复发。
Targeted cancer therapeutics select for drug-resistant rescue subclones (RSCs), which typically carry rescue mutations that restore oncogenic signaling. Whereas mutations underlying antibiotic resistance frequently burden drug-naive microbes with a fitness cost, it remains unknown whether and how rescue mutations underlying cancer relapse encounter negative selection prior to targeted therapy. Here, using mouse models of reversible, Wnt-driven mammary cancer, we uncovered stringent counter-selection against Wnt signaling overdose during the clonal evolution of RSCs. Analyzing recurrent tumors emerging during simulated targeted therapy (Wnt withdrawal) by multi-region DNA sequencing revealed polyclonal relapses comprised of multiple RSCs, which bear distinct but functionally equivalent rescue mutations that converge on sub-maximal Wnt pathway activation. When superimposed on native (i.e., undrugged) signaling, these rescue mutations faced negative selection, indicating that they burden RSCs with a fitness cost before Wnt withdrawal unmasks their selective advantage. Exploiting collateral sensitivity to oncogene overdose may help eliminate RSCs and prevent cancer relapse.